Isoxazole derivatives

ABSTRACT

A compound represented by the formula (I)  
                 
 
wherein one of R 1  and R 2  is a hydrogen atom or a substituent and the other is an optionally substituted cyclic group; 
W is a bond or a divalent aliphatic hydrocarbon group; 
 
Y is a group of the formula: —OR 3  (wherein R is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group) or an optionally esterified or amidated carboxyl group, or a salt thereof or a prodrug thereof has a superior insulin secretion promoting action and a hypoglycemic action and shows low toxicity. Therefore, the compound is useful as a pharmaceutical agent, particularly as an agent for the prophylaxis or treatment of diabetes and diabetic complications, and the like.

TECHNICAL FIELD

The present invention relates to an agent for the prophylaxis ortreatment of diabetes, impaired glucose tolerance or diabeticcomplications, which comprises an isoxazole derivative.

In addition, the present invention relates to an insulin secretagoguecomprising an isoxazole derivative.

Moreover, the present invention relates to a novel isoxazole derivativehaving a superior hypoglycemic action and useful as an agent for theprophylaxis or treatment of diabetes, impaired glucose tolerance,diabetic complications and the like, and a method for the prophylaxis ortreatment of diabetes or diabetic complications, which comprisesadministration of said novel isoxazole derivative to a mammal, as wellas to use of said novel isoxazole derivative for the production of anagent for the prophylaxis or treatment of diabetes or an agent for theprophylaxis or treatment of diabetic complications.

BACKGROUND ART

At present, a sulfonylurea, a biguanide, an α-glucosidase inhibitor andthe like have been used as agents for treating diabetes. While asulfonylurea produces a potent hypoglycemic action, it sometimes causesserious hypoglycemia and requires attention during use. A biguanideeasily causes relatively serious lactic acidosis as a side effect. Anα-glucosidase inhibitor delays digestion and absorption of glucose inthe gastrointestinal tract and suppresses increase in the blood glucoselevel after meal, but side effects of sense of distension, diarrhea andthe like are problematic (JOSLIN'S DIABETES MELLITUS 13Th Edition521-522).

As isoxazole derivatives, for example, the following compounds areknown.(1) JP-B-44-29656 describes that a compound represented by the formula

wherein R is a phenyl group, R′ is a hydrogen or a lower alkyl group, Ais a straight-chain or branched divalent hydrocarbon group having 2 to 5carbon atoms, and Q′ is a hydroxy group, an amino group or an acylaminogroup, has an analgesic action, an antitussive action, an antipyreticaction and an anti-inflammatory action.(2) Japanese Patent Application under PCT laid-open under kohyo No.9-509951 describes that a compound represented by the formula

wherein one of R¹ and R² is 3,5-dimethyl-4-hydroxyphenyl and the otherR¹ or R² is pyridyl etc.; A is a double bond etc.; R⁴ is a hydrogen atometc.; and R³ is a hydrogen atom, (C₁-C₄)-alkyl or hydroxy-(C₁-C₄)-alkyl,is useful for the treatment of inflammation, asthma, rheumatic diseaseand autoimmune disease.(3) WO00/08001 describes that a compound represented by the formula

wherein R¹ and R³ are each an optionally substituted lower alkyl, aryletc., and R² is a hydrogen atom etc., is useful as an estrogen receptormodulator.(4) WO98/28282 describes that a compound represented by the formula

wherein ring M may contain 0 to 2 N-atoms besides J; J is O or S; D isCN etc.; E is phenyl etc.; G is absent or NHCH₂ etc.; Z is C₁₋₄ alkyleneetc.; R^(1a) and R^(1b) are independently absent or —(CH₂)_(r)—R1 (r is0, 1, 2 or 3, R1′ is hydrogen atom etc.) etc.; A is C₃₋₁₀ carbocyclicresidue etc.; B is C₃₋₁₀ carbocycle residue etc.; s is 0, 1 or 2, isuseful as a Xa factor inhibitor.

However, it is not known that the above-mentioned isoxazole derivativesare useful as agents for the prophylaxis or treatment of diabetes orimpaired glucose tolerance, insulin secretagogues and the like.

DISCLOSURE OF THE INVENTION

The present inventors have first found that a compound represented bythe formula (Ia)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W designates a bond ora divalent aliphatic hydrocarbon group; and Y represents the formula:—OR³ (R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group) or an optionally esterified or amidated carboxylgroup, provided that when R¹ or R² is 3,5-di-tert-butyl-4-hydroxyphenyland W is C₁₋₄ alkylene, Y should not be OH, which is structurallycharacterized in that a group represented by the formula: —W—Y [W and Yare as defined above] is bonded at the 4-position of the isoxazole ring,unexpectedly has a superior insulin secretion promoting action and ahypoglycemic action based on the characteristic chemical structure, andis useful as an agent for the prophylaxis or treatment of diabetes,impaired glucose tolerance, diabetic complications and the like, basedon which finding, they have completed the present invention.

Accordingly, the present invention relates to

1) an agent for the prophylaxis or treatment of diabetes, whichcomprises a compound represented by the formula (Ia) or a salt thereofor a prodrug thereof;

2) an agent for the prophylaxis or treatment of impaired glucosetolerance, which comprises a compound represented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group;W is a bond or a divalent aliphatic hydrocarbon group;Y is a group of the formula: —OR³ (wherein R³ is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group or an optionally substituted acyl group) or anoptionally esterified or amidated carboxyl group, or a salt thereof or aprodrug thereof;3) an insulin secretagogue comprising a compound represented by theformula (I) or a salt thereof or a prodrug thereof;4) an agent for the prophylaxis or treatment of diabetic complications,which comprises a compound represented by the formula (I) or a saltthereof or a prodrug thereof;5) the agent of the aforementioned 4), wherein the diabetic complicationis neuropathy;6) a compound represented by the formula (II)

wherein one of R and R is a hydrogen atom and the other is an optionallysubstituted cyclic group;Wa is a divalent aliphatic hydrocarbon group;Y is a group of the formula: —OR³ (wherein R³ is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group or an optionally substituted acyl group) or anoptionally esterified or amidated carboxyl group, provided that when Wais C₁₋₃ alkylene and Y is a group of the formula: —OR³ (wherein R³ is asdefined above) or an optionally methylesterified carboxyl group, R^(1a)should be a hydrogen atom and R^(2a) should be an optionally substitutedcyclic group, except 5-phenyl-4-isoxazolylmethanol and5-phenyl-4-isoxazolylacetic acid, or a salt thereof;7) the compound of the aforementioned 6), wherein the optionallysubstituted cyclic group represented by R^(1a) or R^(2a) is anoptionally substituted aromatic group;8) the compound of the aforementioned 6), wherein R^(1a) is a hydrogenatom and R^(2a) is an optionally substituted cyclic group;9) the compound of the aforementioned 8), wherein R^(2a) is anoptionally substituted aromatic group;10) the compound of the aforementioned 6), wherein Wa is a divalentaliphatic hydrocarbon group having 1 to 4 carbon atoms;11) the compound of the aforementioned 6), wherein Y is an optionallyamidated carboxyl group;12) a prodrug of the compound of the aforementioned 6);13) the compound of the aforementioned 6), which is

-   3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol;-   3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid or a salt    thereof;-   3-[5-(4-chlorophenyl)-4-isoxazolyl]propan-1-ol;-   3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid or a salt thereof;-   3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propan-1-ol;-   3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionic acid or a salt    thereof;-   N-[4-(diethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide;-   N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide;-   N-[4-(dimethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide;-   N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-(5-phenyl-4-isoxazolyl)propionamide;-   N-benzyl-N-[2-(dimethylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide;    or-   N-benzyl-N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide;    14) a pharmaceutical agent comprising the compound of the    aforementioned 6) or a prodrug thereof;    15) a glucose-dependent insulin secretagogue comprising an isoxazole    derivative;    16) a method for the prophylaxis or treatment of diabetes in a    mammal, which comprises administering to said mammal an effective    amount of a compound represented by the formula (Ia) or a salt    thereof or a prodrug thereof;    17) a method for the prophylaxis or treatment of diabetic    complication in a mammal, which comprises administering to said    mammal an effective amount of a compound represented by the    formula (I) or a salt thereof or a prodrug thereof;    18) a method for the prophylaxis or treatment of impaired glucose    tolerance in a mammal, which comprises administering to said mammal    an effective amount of a compound represented by the formula (I) or    a salt thereof or a prodrug thereof;    19) a method for promoting an insulin secretion in a mammal, which    comprises administering to said mammal an effective amount of a    compound represented by the formula (I) or a salt thereof or a    prodrug thereof;    20) use of a compound represented by the formula (Ia) or a salt    thereof or a prodrug thereof for the production of an agent for the    prophylaxis or treatment of diabetes;    21) use of a compound represented by the formula (I) or a salt    thereof or a prodrug thereof for the production of an agent for the    prophylaxis or treatment of diabetic complications;    22) use of a compound represented by the formula (I) or a salt    thereof or a prodrug thereof for the production of an agent for the    prophylaxis or treatment of impaired glucose tolerance;    23) use of a compound represented by the formula (I) or a salt    thereof or a prodrug thereof for the production of an insulin    secretagogue;    24) a commercial-package comprising the agent for the prophylaxis or    treatment of diabetes according to the aforementioned 1) and written    matter associated therewith, the written matter stating that the    agent can or should be used for the prophylaxis or treatment of    diabetes;    25) a commercial package comprising the agent for the prophylaxis or    treatment of impaired glucose tolerance according to the    aforementioned 2) and written matter associated therewith, the    written matter stating that the agent can or should be used for the    prophylaxis or treatment of impaired glucose tolerance;    26) a commercial package comprising the insulin secretagogue of the    aforementioned 3) and written matter associated therewith, the    written matter stating that the agent can or should be used for    promoting insulin secretion;    27) a commercial package comprising the agent for the prophylaxis or    treatment of diabetic complications according to the    aforementioned 4) and written matter associated therewith, the    written matter stating that the agent can or should be used for the    prophylaxis or treatment of diabetic complications; and the like.

DETAILED DESCRIPTION OF THE INVENTION

The compound represented by the formula (I), (Ia) or (II) is describedin detail in the following.

(1) Definition of R¹ and R²

In the formulas (I) and (Ia), the “cyclic group” of the “optionallysubstituted cyclic group” represented by R¹ or R² is exemplified byalicyclic hydrocarbon group, aromatic hydrocarbon group, aromaticheterocyclic group, non-aromatic heterocyclic group and the like.

Said alicyclic hydrocarbon groups include saturated or unsaturatedalicyclic hydrocarbon groups containing 3 to 12 carbon atoms, such ascycloalkyl groups, cycloalkenyl groups and cycloalkadienyl groups.

Preferable examples of the cycloalkyl groups are C₃₋₁₀ cycloalkyl groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.

Preferable examples of the cycloalkenyl groups are C₃₋₁₀ cycloalkenylgroups such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yland 3-cyclohexen-1-yl.

Preferable examples of the cycloalkadienyl groups are C₄₋₁₀cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl.

As the aromatic hydrocarbon group, an aromatic hydrocarbon group having6 to 14 carbon atoms (e.g., aryl group etc.) is exemplified. Preferableexamples of the aromatic hydrocarbon group include phenyl, naphthyl,anthryl, phenanthryl, acenaphthylenyl, biphenylyl, indenyl and the like,with preference given to phenyl, 1-naphthyl, 2-naphthyl and the like.The aromatic hydrocarbon group may be partially saturated, and examplesof the partially saturated aromatic hydrocarbon group (aryl group having6 to 14 carbon atoms) include dihydroindenyl and the like.

As the non-aromatic heterocyclic group, a 5 to 7-membered monocyclicnon-aromatic heterocyclic group containing, besides carbon atom, 1 to 4hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom,as a ring constituting atom, or non-aromatic fused heterocyclic group isexemplified. Examples of the non-aromatic fused heterocyclic groupinclude a group obtained by condensation of these 5 to 7-memberedmonocyclic non-aromatic heterocyclic groups with a 6-membered ringcontaining 1 or 2 nitrogen atoms, benzene ring or a 5-membered ringcontaining one sulfur atom, and the like.

Preferable examples of the non-aromatic heterocyclic group includepyrrolidinyl (e.g., 1-pyrrolidinyl), piperidinyl (e.g., piperidino),morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino),piperazinyl (e.g., 1-piperazinyl), hexamethyleneiminyl (e.g.,hexamethyleneimin-1-yl), oxazolidinyl (e.g., oxazolidin-3-yl),thiazolidinyl (e.g., thiazolidin-3-yl), imidazolidinyl (e.g.,imidazolidin-3-yl), oxoimidazolidinyl (e.g., 2-oxoimidazolidin-1-yl),dioxoimidazolidinyl (e.g., 2,4-dioxoimidazolidin-3-yl),dioxooxazolidinyl (e.g., 2,4-dioxooxazolidin-3-yl), dioxothiazolidinyl(e.g., 2,4-dioxothiazolidin-3-yl), tetrahydrofuranyl, azepanyl,tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridin-1-yl) and the like.

As the aromatic heterocyclic group, a 5 to 7-membered monocyclicaromatic heterocyclic group containing, besides carbon atom, 1 to 4hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom,as a ring constituting atom, or fused aromatic heterocyclic group isexemplified. As the fused aromatic heterocyclic group, a group obtainedby condensation of these 5 to 7-membered monocyclic aromaticheterocyclic groups with a 6-membered ring containing 1 or 2 nitrogenatoms, benzene ring or a 5-membered ring containing one sulfur atom, andthe like

Specific examples of the aromatic heterocyclic group include furyl(e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl(e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl),pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl, isothiazolyl,thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl (e.g.,1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g.,1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl),quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), quinazolyl (e.g.,2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl), benzofuryl(e.g., 2-benzofuryl, 3-benzofuryl), benzothienyl (e.g., 2-benzothienyl,3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzothiazolyl(e.g., 2-benzothiazolyl), benzimidazoyl (e.g., benzimidazol-1-yl,benzimidazol-2-yl), indolyl (e.g., indol-1-yl, indol-3-yl), 1H-indazolyl(e.g., 1H-indazol-3-yl), 1H-pyrrolo[2,3-b]pyrazinyl (e.g.,1H-pyrrolo[2,3-b]pyrazin-2-yl), 1H-pyrrolopyridinyl (e.g.,1H-pyrrolo[2,3-b]pyridin-6-yl), 1H-imidazopyridinyl (e.g.,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl),1H-imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), triazinyl,isoquinolyl, benzothiadiazolyl and the like.

The aromatic heterocyclic group is preferably a 5 or 6-membered aromaticheterocyclic group optionally condensed with a benzene ring (preferablyfuryl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl,oxadiazolyl, benzoxazolyl, benzothiazolyl, quinolyl) and the like. The“cyclic group” is preferably an aromatic group such as aromatichydrocarbon group, aromatic heterocyclic group and the like, morepreferably aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g.,aryl group etc.). Particularly, phenyl is preferable.

In the formulas (I) and (Ia), the “cyclic group” represented by R¹ or R²optionally has 1 to 5, preferably 1 to 3, substituents at asubstitutable position(s) on the cyclic group. Examples of suchsubstituent include “halogen atom”, “nitro group”, “cyano group”, “C₁₋₃alkylenedioxy group”, “optionally substituted aliphatic hydrocarbongroup”, “optionally substituted alicyclic hydrocarbon group”,“optionally substituted aromatic hydrocarbon group”, “optionallysubstituted heterocyclic group”, “optionally substituted acyl group”,“optionally substituted amino group”, “optionally substituted hydroxygroup”, “optionally substituted thiol group”, “optionally esterified oramidated carboxyl group” and the like.

As the “halogen atom”, fluorine, chlorine, bromine and iodine areexemplified. Of these, fluorine and chlorine are preferable.

As the “C₁₋₃ alkylenedioxy group”, methylenedioxy and ethylenedioxy areexemplified.

Said aliphatic hydrocarbon groups in the “optionally substitutedaliphatic hydrocarbon group” include straight-chain or branchedaliphatic hydrocarbon groups containing 1 to 15 carbon atoms, such asalkyl groups, alkenyl groups, alkynyl groups, and the like.

Preferable examples of the alkyl groups are C₁₋₁₀ alkyl groups such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2,-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl, heptyl, octyl, nonyl and decyl.

Preferable examples of the alkenyl groups are C₂₋₁₀ alkenyl groups suchas ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl, 1-heptenyl, 1-octenyl and the like.

Preferable examples of the alkynyl groups are C₂₋₁₀ alkynyl groups suchas ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.

As the substituent of the “optionally substituted aliphatic hydrocarbongroup”, for example, cycloalkyl group having 3 to 10 carbon atoms, arylgroup having 6 to 14 carbon atoms (e.g., phenyl, naphthyl and the like),aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl,thiazolyl and the like), non-aromatic heterocyclic group (e.g.,tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl,piperazinyl and the like), aralkyl group having 7 to 13 carbon atoms,amino group, amino group mono- or di-substituted by alkyl having 1 to 4carbon atoms or acyl group having 2 to 8 carbon atoms (e.g., alkanoylgroup and the like), amidino group, acyl group having 2 to 8 carbonatoms (e.g., alkanoyl group and the like), carbamoyl group, carbamoylgroup mono- or di-substituted by alkyl having 1 to 4 carbon atoms,sulfamoyl group, sulfamoyl group mono- or di-substituted by alkyl having1 to 4 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 8carbon atoms, hydroxy group, alkoxy group having 1 to 6 carbon atomswhich is optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), alkenyloxy group having 2 to 5carbon atoms which is optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like), cycloalkyloxygroup having 3 to 7 carbon atoms, aralkyloxy group having 7 to 13 carbonatoms, aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy,naphthyloxy and the like), thiol group, alkylthio group having 1 to 6carbon atoms which is optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like), aralkylthiogroup having 7 to 13 carbon atoms, arylthio group having 6 to 14 carbonatoms (e.g., phenylthio, naphthylthio and the like), sulfo group, cyanogroup, azide group, nitro group, nitroso group, halogen atom (e.g.,fluorine, chlorine, bromine, iodine) and the like. The number of thesubstituent is, for example, 1 to 3.

Examples of the alicyclic hydrocarbon group and aromatic hydrocarbongroup of the “optionally substituted alicyclic hydrocarbon group” and“optionally substituted aromatic hydrocarbon group” respectively includethose exemplified as the “cyclic group” represented by R¹ or R².

As the heterocyclic group of the “optionally substituted heterocyclicgroup”, the aromatic heterocyclic group and non-aromatic heterocyclicgroup exemplified as the “cyclic group” represented by R¹ or R² areexemplified.

As the substituent of the aforementioned “optionally substitutedalicyclic hydrocarbon group”. “optionally substituted aromatichydrocarbon group” and “optionally substituted heterocyclic group”,alkyl group having 1 to 6 carbon atoms which is optionally substitutedby 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine andthe like), alkenyl group having 2 to 6 carbon atoms which is optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like), cycloalkyl group having 3 to 10 carbon atoms, arylgroup having 6 to 14 carbon atoms (e.g., phenyl, naphthyl and the like),aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl,thiazolyl and the like), non-aromatic heterocyclic group (e.g.,tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl,piperazinyl and the like), aralkyl group having 7 to 13 carbon atoms,amino group, amino group mono- or di-substituted by alkyl having 1 to 4carbon atoms or acyl group having 2 to 8 carbon atoms (e.g., alkanoylgroup and the like), amidino group, acyl group having 2 to 8 carbonatoms (e.g., alkanoyl group and the like), carbamoyl group, carbamoylgroup mono- or di-substituted by alkyl having 1 to 4 carbon atoms,sulfamoyl group, sulfamoyl group mono- or di-substituted by alkyl having1 to 4 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 8carbon atoms, hydroxy group, alkoxy group having 1 to 6 carbon atomswhich is optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), alkenyloxy group having 2 to 5carbon atoms which is optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like), cycloalkyloxygroup having 3 to 7 carbon atoms, aralkyloxy group having 7 to 13 carbonatoms, aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy,naphthyloxy and the like), thiol group, alkylthio group having 1 to 6carbon atoms which is optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like), aralkylthiogroup having 7 to 13 carbon atoms, arylthio group having 6 to 14 carbonatoms (e.g., phenylthio, naphthylthio and the like), sulfo group, cyanogroup, azide group, nitro group, nitroso group, halogen atom (e.g.,fluorine, chlorine, bromine, iodine) and the like. The number of thesubstituent is, for example, 1 to 3.

The acyl group of the “optionally substituted acyl group” is an acylgroup having 1 to 13 carbon atoms, which is specifically formyl, a grouprepresented by the formula: —COR⁴, —SO₂R⁴, —SOR⁴ or —PO₃R⁴R⁵, wherein R⁴and R⁵ are the same or different and each is hydrocarbon group oraromatic heterocyclic group, and R⁴ and R⁵ may form a heterocycletogether with the adjacent oxo-substituted phosphorus atom and twooxygen atoms, and the like.

The hydrocarbon group represented by R⁴ or R⁵ is exemplified byaliphatic hydrocarbon group, alicyclic hydrocarbon group, aromatichydrocarbon group, aromatic aliphatic hydrocarbon group and the like.

The aliphatic hydrocarbon group is exemplified by the “aliphatichydrocarbon group” of the “optionally substituted aliphatic hydrocarbongroup” exemplified as a substituent for the “cyclic group” representedby R¹ or R².

The alicyclic hydrocarbon group and aromatic hydrocarbon group arerespectively exemplified by those exemplified as “cyclic group”represented by R¹ or R².

The aromatic aliphatic hydrocarbon group is exemplified by aromaticaliphatic hydrocarbon group having 7 to 13 carbon atoms, such as aralkylgroup, arylalkenyl group and the like.

Preferable examples of the aralkyl group include aralkyl group having 7to 13 carbon atoms, such as benzyl, phenethyl, naphthylmethyl,benzhydryl and the like.

Preferable examples of the arylalkenyl group include arylalkenyl grouphaving 8 to 13 carbon atoms, such as styryl and the like.

The hydrocarbon group is preferably alkyl group having 1 to 10 carbonatoms, alkenyl group having 2 to 10 carbon atoms, cycloalkyl grouphaving 3 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbonatoms, aryl group having 6 to 12 carbon atoms, aralkyl group having 7 to13 carbon atoms and the like.

The aromatic heterocyclic group represented by R⁴ or R⁵ is exemplifiedby those exemplified as the “cyclic group” represented by R¹ or R². Ofthose, for example, thienyl, furyl, pyridyl and the like are preferable.

The heterocycle formed by R⁴ and R⁵ with the adjacent oxo-substitutedphosphorus atom and two oxygen atoms is exemplified by a 4 to 7-memberedheterocycle containing, besides carbon atom, oxo-substituted phosphorusatom and two oxygen atoms, and optionally further having 1 or 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom, as ringconstituting atom, and the like. Specific examples of the heterocycleinclude 2-oxide-1,3,2-dioxaphosphinane; 2-oxide-1,3,2-dioxaphophoraneand the like.

Preferable examples of the acyl group include alkanoyl group having 2 to10 carbon atoms (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl), alkenoyl grouphaving 3 to 10 carbon atoms (e.g., crotonyl), cycloalkanoyl group having4 to 10 carbon atoms (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl), cycloalkanoyl group having 4to 10 carbon atoms (e.g., 2-cyclohexenecarbonyl), arylcarbonyl grouphaving 7 to 13 carbon atoms (e.g., benzoyl), aromatic heterocycliccarbonyl (e.g., nicotinoyl, isonicotinoyl), alkylsulfinyl group having 1to 10 carbon atoms (e.g., methylsulfinyl, ethylsulfinyl), alkylsulfonylgroup having 1 to 10 carbon atoms (e.g., methylsulfonyl, ethylsulfonyl),(mono- or di(C₁-C₁₀)alkyl)phosphono group which may form a ring (e.g.,dimethylphosphono; diethylphosphono; diisopropylphosphono;dibutylphosphono; 2-oxide-1,3,2-dioxaphosphinanyl) and the like.

The acyl group may have 1 to 3 substituents at a substitutableposition(s). Examples of the substituent include C₁₋₆ alkyl group (e.g.,methyl, ethyl and the like) optionally substituted by 1 to 3 halogenatoms (e.g., fluorine, chlorine, iodine and the like), C₁₋₆ alkoxy group(e.g., methoxy, ethoxy and the like) optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like),halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like),nitro, hydroxy, amino and the like.

The “optionally substituted amino group” is exemplified by amino groupoptionally mono- or di-substituted by alkyl group having 1 to 10 carbonatoms, alkenyl group having 2 to 10 carbon atoms, cycloalkyl grouphaving 3 to 10 carbon atoms, cycloalkenyl group having 3 to 10 carbonatoms, aryl group having 6 to 14 carbon atoms, acyl group having 1 to 13carbon atoms and the like.

The alkyl group having 1 to 10 carbon atoms and alkenyl group having 2to 10 carbon atoms are respectively exemplified by those exemplified asthe substituents of “cyclic group” represented by R¹ or R².

The cycloalkyl group having 3 to 10 carbon atoms, cycloalkenyl grouphaving 3 to 10 carbon atoms and aryl group having 6 to 14 carbon atomsare respectively exemplified by those exemplified as “cyclic group”represented by R¹ or R².

The acyl group having 1 to 13 carbon atoms is exemplified by thoseexemplified as acyl group of the aforementioned “optionally substitutedacyl group”, preferably alkanoyl group having 2 to 10 carbon atoms,arylcarbonyl group having 7 to 13 carbon atoms and the like.

The substituted amino group is exemplified by mono- or di-C₁₋₁₀alkylamino (e.g., methylamino, dimethylamino, ethylamino, diethylamino,ethylmethylamino, propylamino, dibutylamino), mono- or di-C₂₋₁₀alkenylamino (e.g., diallylamino), mono- or di-C₃₋₁₀ cycloalkylamino(e.g., cyclohexylamino), mono- or di-C₂₋₁₀ alkanoylamino (e.g.,acetylamino, propionylamino), arylcarbonylamino group having 7 to 13carbon atoms (e.g., benzoylamino), arylamino having 6 to 14 carbon atoms(e.g., phenylamino), N-C₁₋₁₀ alkyl-N-C₆₋₁₄ arylamino (e.g.,N-methyl-N-phenylamino) and the like.

The “optionally substituted hydroxy group” is exemplified by hydroxygroup optionally substituted by “alkyl group having 1 to 10 carbonatoms”, “alkenyl group having 2 to 10 carbon atoms”, “cycloalkyl grouphaving 3 to 10 carbon atoms”, “cycloalkenyl group having 3 to 10 carbonatoms”, “aryl group having 6 to 14 carbon atoms”, “aralkyl having 7 to13 carbon atoms”, “acyl group having 1 to 13 carbon atoms” or“heteroaryl group”, each being optionally substituted.

As used herein, the “alkyl group having 1 to 10 carbon atoms”, “alkenylgroup having 2 to 10 carbon atoms” and “acyl group having 1 to 13 carbonatoms” are respectively exemplified by those exemplified as thesubstituent of the “cyclic group” represented by R¹ or R².

Examples of the “cycloalkyl group having 3 to 10 carbon atoms”,“cycloalkenyl group having 3 to 10 carbon atoms” and “aryl group having6 to 14 carbon atoms” include those exemplified as “cyclic group”represented by R¹ or R².

The “aralkyl having 7 to 13 carbon atoms” is exemplified by benzyl,phenethyl, naphthylmethyl, naphthylethyl and the like.

These “alkyl group having 1 to 10 carbon atoms”, “alkenyl group having 2to 10 carbon atoms”, “cycloalkyl group having 3 to 10 carbon atoms”,“cycloalkenyl group having 3 to 10 carbon atoms”, “aryl group having 6to 14 carbon atoms”, “aralkyl having 7 to 13 carbon atoms” and “acylgroup having 1 to 13 carbon atoms” may have 1 or 2 substituents at asubstitutable position(s), wherein the substituent is exemplified byhalogen atom (e.g., fluorine, chlorine, bromine, iodine and the like),alkoxy group having 1 to 3 carbon atoms (e.g., methoxy, ethoxy and thelike) and the like.

The “heteroaryl group” is exemplified by the aromatic heterocyclic groupexemplified as the “optionally substituted cyclic group” represented byR¹ or R². Of those, pyridyl, imidazolyl, triazolyl and the like arepreferable.

The substituted hydroxy group is exemplified by alkoxy group, alkenyloxygroup, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group,aralkyloxy group, acyloxy group, heteroaryloxy group, each beingoptionally substituted, and the like.

Preferable examples of the alkoxy groups are C₁₋₁₀ alkoxy groups such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy,nonyloxy and the like.

Preferable examples of the alkenyloxy groups are C₂₋₁₀ alkenyloxy groupssuch as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like.

Preferable examples of the cycloalkyloxy group include cycloalkyloxygroup having 3 to 10 carbon atoms, such as cyclobutoxy, cyclopentyloxy,cyclohexyloxy and the like.

Preferable examples of the cycloalkenyloxy group include cycloalkenyloxygroup having 3 to 10 carbon atoms, such as 2-cyclopentenyloxy,2-cyclohexenyloxy and the like.

Preferable examples of the aryloxy group include aryloxy group having 6to 14 carbon atoms, such as phenoxy, naphthyloxy and the like.

Preferable examples of the aralkyloxy group include aralkyloxy grouphaving 7 to 13 carbon atoms, such as benzyloxy, phenethyloxy,naphthylmethyloxy and the like.

Preferable examples of the acyloxy groups are C₂₋₁₃ acyloxy groups, suchas C₂₋₄ alkanoyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy,isobutyryloxy and the like) and the like.

Preferable examples of the heteroaryloxy group include a 5 to 7-memberedmonocyclic heteroaryloxy group, such as 2-pyridyloxy, 3-pyridyloxy,2-imidazolyloxy, 1,2,4-triazol-5-yloxy and the like.

The above-mentioned alkoxy group, alkenyloxy group, cycloalkyloxy group,cycloalkenyloxy group, aryloxy group, aralkyloxy group, acyloxy groupand heteroaryloxy group may have 1 or 2 substituents at a substitutableposition(s). Examples of the substituent include halogen atom (e.g.,fluorine, chlorine, bromine, iodine and the like), C₁₋₆ alkoxy group(e.g., methoxy, ethoxy and the like) optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like),hydroxy, nitro, amino and the like. For example, 4-chlorophenoxy,2-methoxyphenoxy and the like are mentioned as substituted aryloxygroup.

Examples of the optionally substituted thiol group include a thiol groupoptionally substituted by “alkyl group having 1 to 10 carbon atoms”,“alkenyl group having 2 to 10 carbon atoms”, “cycloalkyl group having 3to 10 carbon atoms”, “cycloalkenyl group having 3 to 10 carbon atoms”,“aryl group having 6 to 14 carbon atoms”, “aralkyl having 7 to 13 carbonatoms”, “acyl group having 1 to 13 carbon atoms”, “heteroaryl group” andthe like.

As used herein, the “alkyl group having 1 to 10 carbon atoms”, “alkenylgroup having 2 to 10 carbon atoms”, “cycloalkyl group having 3 to 10carbon atoms”, “cycloalkenyl group having 3 to 10 carbon atoms”, “arylgroup having 6 to 14 carbon atoms”, “aralkyl having 7 to 13 carbonatoms”, “acyl group having 1 to 13 carbon atoms” and “heteroaryl group”are exemplified by those exemplified for the aforementioned “optionallysubstituted hydroxy group”.

The substituted thiol group is exemplified by alkylthio, alkenylthio,cycloalkylthio, cycloalkenylthio, arylthio, aralkylthio, acylthio,heteroarylthio and the like.

Preferable examples of the alkylthio group include alkylthio grouphaving 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio,pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio,nonylthio and the like.

Preferable examples of the alkenylthio group include alkenylthio grouphaving 2 to 10 carbon atoms, such as allylthio, crotylthio,2-pentenylthio, 3-hexenylthio and the like.

Preferable examples of the cycloalkylthio group include cycloalkylthiogroup having 3 to 10 carbon atoms, such as cyclobutylthio,cyclopentylthio, cyclohexylthio and the like.

Preferable examples of the cycloalkenylthio group includecycloalkenylthio group having 3 to 10 carbon atoms, such as2-cyclopentenylthio, 2-cyclohexenylthio and the like.

Preferable examples of the arylthio group include arylthio group having6 to 14 carbon atoms, such as phenylthio, naphthylthio and the like.

Preferable examples of the aralkylthio group include aralkylthio grouphaving 7 to 13 carbon atoms, such as benzylthio, phenethylthio,naphthylmethylthio and the like.

Preferable examples of the acylthio group include, acylthio group having2 to 13 carbon atoms, such as alkanoylthio group having 2 to 4 carbonatoms (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio andthe like), and the like.

Preferable examples of the heteroarylthio group include 5 to 7-memberedmonocyclic heteroarylthio group, such as 2-pyridylthio, 3-pyridylthio,2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like.

In the optionally esterified carboxyl group, examples of the esterifiedcarboxyl group include alkoxycarbonyl group having 2 to 5 carbon atoms(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyland the like), aralkyloxycarbonyl group having 8 to 14 carbon atoms(e.g., benzyloxycarbonyl and the like), aryloxycarbonyl group having 7to 15 carbon atoms (e.g., phenoxycarbonyl, p-tolyloxycarbonyl and thelike) optionally substituted by 1 or 2 alkyl group having 1 to 3 carbonatoms and the like.

In the optionally amidated carboxyl group, the amidated carboxyl groupis, for example, a group of the formula: —CON(R⁶) (R⁷) wherein R⁶ and R⁷are the same or different and each is a hydrogen atom, an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup, or R⁶ and R⁷ may form, together with the adjacent nitrogen atom,an optionally substituted nitrogen-containing heterocycle.

Here, the hydrocarbon group of the “optionally substituted hydrocarbongroup” represented by R⁶ or R⁷ is exemplified by the hydrocarbon groupexemplified for the aforementioned R⁴. The hydrocarbon group ispreferably alkyl group having 1 to 10 carbon atoms (preferably methyl,ethyl, propyl, butyl, tert-butyl, pentyl, 1-ethylpropyl,2,2-dimethylpropyl); alkynyl group having 2 to 10 carbon atoms(preferably 2-propynyl); cycloalkyl group having 3 to 10 carbon atoms(preferably cyclopropyl, cyclohexyl) optionally condensed with benzenering; aryl group having 6 to 14 carbon atoms (preferably phenyl,dihydroindenyl, biphenylyl) optionally condensed with cycloalkane having3 to 10 carbon atoms (preferably cyclopentane); aralkyl group having 7to 13 carbon atoms (preferably benzyl, phenethyl, phenylpropyl,naphthylmethyl, benzhydryl) and the like.

The heterocyclic group of the “optionally substituted heterocyclicgroup” represented by R⁶ and R⁷ is exemplified by aromatic heterocyclicgroup and non-aromatic heterocyclic group exemplified for “cyclic group”represented by R¹ or R². The heterocyclic group is preferably thiazolyl,oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl,triazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolyl,isoquinolyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl and thelike.

The hydrocarbon group and heterocyclic group may have 1 to 4 (preferably1 to 3) substituents at a substitutable position(s), and examples of thesubstituent include halogen atom (e.g., fluorine, chlorine, bromine,iodine and the like); C₁₋₆ alkyl group (e.g., methyl, trifluoromethyland the like) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like); C₁₋₆ alkoxy group(e.g., methoxy, isopropoxy, trifluoromethoxy and the like) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like); nitro; hydroxy; amino; carbamoyl group; (mono- ordi-C₁₋₆ alkyl-phosphono optionally forming a ring)-C₁₋₆ alkyl group[e.g., dimethylphosphonomethyl, diethylphosphonomethyl,diisopropylphosphonomethyl, dibutylphosphonomethyl,diethylphosphonoethyl, (2-oxide-1,3,2-dioxaphosphinanyl)methyl,(methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(dimethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(diethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-ethyl-5-methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl and the like];phosphono-C₁₋₆ alkyl group (e.g., phosphonomethyl and the like); C₂₋₅alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and thelike); C₂₋₅ alkoxycarbonyl-C₁₋₆ alkyl group (e.g., ethoxycarbonylmethyland the like); C₆₋₁₀ aryl group (e.g., phenyl and the like) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like), C₁₋₆ alkoxy group or carbamoyl group; heterocyclicgroup (e.g., indolyl, imidazolyl, pyridyl, morpholino, furyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and the like)optionally substituted by C₁₋₆ alkyl group (e.g., methyl and the like)or oxo group; C₁₋₆ alkyl-heterocyclic-C₁₋₆ alkoxy group (e.g.,ethyltriazolylethoxy and the like); mono- or di-C₁₋₆ alkylamino group(e.g., dimethylamino, diethylamino, ethylmethylamino, diisopropylamino,N-methyl-N-phenylamino, di-hydroxyethyl-amino and the like) optionallysubstituted by hydroxy group, C₆₋₁₀ aryl group (e.g., phenyl and thelike) or C₁₋₆ alkyl-C₆₋₁₀ aryl group (e.g., methylphenyl and the like);C₆₋₁₀ arylamino group (e.g., phenylamino and the like); C₃₋₁₀ cycloalkylgroup (e.g., cyclohexyl and the like); C₁₋₃ alkylenedioxy group (e.g.,methylenedioxy, ethylenedioxy and the like); C₁₋₆ alkylthio group (e.g.,methylthio and the like) optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like); C₇₋₁₃ aralkylgroup (e.g., benzyl and the like); aromatic heterocyclic amino group(e.g., pyridylamino and the like) optionally substituted by nitro group;C₆₋₁₀ aryloxy group (e.g., phenoxy and the like); mono- or di-C₁₋₆alkyl-phosphono group (e.g., diethylphosphono and the like); mono- ordi-(mono- or di-C₁₋₆ alkyl-phosphono)-C₂₋₆ alkenyl group [e.g.,bis(diethylphosphono)ethenyl, 2-diethylphosphono-2-ethoxycarbonylethenyland the like] optionally substituted by C₂₋₅ alkoxycarbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl and the like); bis(mono- or di-C₁₋₆alkylamino)-phosphoryl-C₁₋₆ alkyl group (e.g., bis(ethylamino)phosphorylmethyl and the like); oxo group and the like.

The nitrogen-containing heterocycle formed by R⁶ and R⁷ together withthe adjacent nitrogen atom is exemplified by a 5 to 8-membered(preferably 5 to 7-membered) nitrogen-containing (preferably saturated)heterocyclic group containing, besides carbon atom, at least onenitrogen atom and optionally 1 or 2 hetero atoms selected from oxygenatom, sulfur atom and nitrogen atom, as ring constituting atom.Preferable examples of the nitrogen-containing heterocyclic groupinclude 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl,1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl,1-azepanyl, 1-azocanyl and the like. The nitrogen-containingheterocyclic group may form a fused ring group with benzene ring orC₃₋₁₀ cycloalkane (e.g., cyclohexane), and examples of the fused ringgroup include tetrahydroisoquinolin-2-yl, decahydroisoquinolin-2-yl andthe like.

The nitrogen-containing heterocyclic group may have 1 or 2 substituentsat a substitutable position(s). Examples of such substituent includeC₁₋₆ alkyl group (e.g., methyl, ethyl and the like) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like), hydroxy group, C₂₋₇ alkoxycarbonyl group (e.g.,ethoxycarbonyl) or 5 or 6-membered nitrogen-containing heterocyclicgroup (e.g., pyrrolidinyl and the like); C₇₋₁₄ aralkyl group (e.g.,benzyl, diphenylmethyl, benzhydryl and the like) optionally substitutedby C₁₋₃ alkylenedioxy group (e.g., methylenedioxy and the like); C₆₋₁₄aryl group (e.g., phenyl and the like) optionally substituted by C₁₋₆alkyl group (e.g., methyl, trifluoromethyl and the like) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like), halogen atom (e.g., fluorine, chlorine, bromine,iodine and the like), C₁₋₆ alkoxy group (e.g., methoxy, ethoxy and thelike) or C₂₋₁₀ alkanoyl group (e.g., acetyl and the like); C₆₋₁₄aryl-C₂₋₆ alkenyl group (e.g., phenylpropenyl and the like); C₆₋₁₄arylamino-C₁₋₆ alkyl group (e.g., phenylaminomethyl and the like)optionally substituted by C₁₋₆ alkyl group (e.g., methyl and the like);cyano group; oxo group; hydroxy group; mono- or di-C₂₋₁₀ alkanoylaminogroup (e.g., acetylamino, trifluoroacetylamino, propionylamino,N-acetyl-N-ethylamino and the like) optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like)or C₁₋₆ alkyl group (e.g., methyl, ethyl and the like); C₂₋₇alkoxycarbonylamino group (e.g., tert-butoxycarbonylamino and the like);5 or 6-membered nitrogen-containing heterocyclic group (e.g., pyridyl,piperidinyl, pyrimidinyl, pyrrolidinyl and the like); aromaticheterocyclic carbonyl group (e.g., furoyl and the like); carbamoylgroup; C₂₋₁₀ alkanoyl group (e.g., acetyl and the like); C₂₋₇alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and thelike); and the like.

The “substituent” of the “optionally substituted cyclic group”represented by R¹ or R² is preferably

1) halogen atom (e.g., fluorine, chlorine, bromine, iodine and thelike);

2) alkyl group having 1 to 6 carbon atoms (e.g., methyl, trifluoromethyland the like) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like);

3) alkoxy group having 1 to 6 carbon atoms (e.g., methoxy,trifluoromethoxy and the like) optionally substituted by 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine and the like);

4) alkylthio group having 1 to 6 carbon atoms (e.g., methylthio and thelike) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like);

5) nitro group;

6) cyano group;

7) C₁₋₃ alkylenedioxy group (e.g., methylenedioxy and the like);

8) aryl group having 6 to 14 carbon atoms (e.g., phenyl and the like);

9) alkylsulfinyl group having 1 to 6 carbon atoms (e.g., methylsulfinyland the like);

10) alkylsulfonyl group having 1 to 6 carbon atoms (e.g., methylsulfonyland the like); and the like. The number of the substituent is preferably1 to 3, more preferably 1 or 2.

The “substituent” is more preferably 1 or 2 selected from

1) halogen atom (e.g., fluorine, chlorine, bromine, iodine and thelike);

2) alkyl group having 1 to 6 carbon atoms (e.g., methyl, trifluoromethyland the like) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like);

3) alkoxy group having 1 to 6 carbon atoms (e.g., methoxy,trifluoromethoxy and the like) optionally substituted by 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine and the like);

4) nitro group;

5) cyano group; and the like.

The “optionally substituted cyclic group” represented by R or R² ispreferably an optionally substituted aromatic group, more preferablyaromatic hydrocarbon group (preferably phenyl, naphthyl) or aromaticheterocyclic group (preferably furyl, thienyl, pyridyl, quinolyl, morepreferably thienyl, pyridyl) optionally having 1 to 3 substituentsselected from

1) halogen atom (e.g., fluorine, chlorine, bromine, iodine);

2) alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl,trifluoromethyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

3) alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy,trifluoromethoxy) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

4) alkylthio group having 1 to 6 carbon atoms (e.g., methylthio)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine);

5) nitro group;

6) cyano group;

7) C₁₋₃ alkylenedioxy group (e.g., methylenedioxy);

8) aryl group having 6 to 14 carbon atoms (e.g., phenyl);

9) alkylsulfinyl group having 1 to 6 carbon atoms (e.g.,methylsulfinyl); and

10) alkylsulfonyl group having 1 to 6 carbon atoms (e.g.,methylsulfonyl).

The “optionally substituted cyclic group” represented by R¹ or R² isparticularly preferably C₆₋₁₄ aryl group (preferably phenyl) optionallyhaving 1 to 3 halogen atoms (preferably fluorine, chlorine, bromine).

In the formulas (I) and (Ia), the “substituent” represented by R¹ or R²is exemplified by those exemplified as the “substituent” of “optionallysubstituted cyclic group” represented by R¹ or R².

The substituent is preferably

1) alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl,trifluoromethyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

2) hydroxy group;

3) aryl group having 6 to 14 carbon atoms (e.g., phenyl); and the like.

In the formulas (I) and (Ia), R¹ is preferably a hydrogen atom or asubstituent and R² is preferably an optionally substituted cyclic group.It is more preferable that R¹ be a hydrogen atom, and R² be anoptionally substituted cyclic group.

(2) Definition of R^(1a) and R^(2a)

In the formula (II), the “optionally substituted cyclic group”represented by R^(1a) or R^(2a) is exemplified by those exemplified forR¹ or R² of the formulas (I) and (Ia)

In the formula (II), R^(1a) is preferably a hydrogen atom and R^(2a) ispreferably an optionally substituted cyclic group. Moreover, R^(2a) ispreferably an optionally substituted aromatic group, particularlypreferably C₆₋₁₄ aryl group (preferably phenyl) optionally having 1 to 3halogen atoms (preferably fluorine, chlorine, bromine).

(3) Definition of W and Wa

In the formulas (I), (Ia) and (II), “divalent aliphatic hydrocarbongroup” represented by W or Wa may be straight-chain or branched, andsaturated or unsaturated.

The “divalent aliphatic hydrocarbon group” is preferably a divalentaliphatic hydrocarbon group having 1 to 8 carbon atoms, which isspecifically exemplified by

(1) C₁₋₈ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—, —CH(CH₃)—, —C(CH₃)₂—, —(CH(CH₃))₂—,—(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like);

(2) C₂₋₈ alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—, —C(CH₃)₂—CH═CH—,—CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— andthe like) and the like.

The “divalent aliphatic hydrocarbon group” is preferably a divalentaliphatic hydrocarbon group having 1 to 4 carbon atoms, and it is morepreferably saturated. Particularly, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—and the like are preferable, of which —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— andthe like are preferable.

In the formulas (I) and (Ia), a compound wherein W is a “divalentaliphatic hydrocarbon group” has a superior hypoglycemic action ascompared to a compound wherein W is a bond. Therefore, W is preferably adivalent aliphatic hydrocarbon group.

W and Wa are preferably a divalent aliphatic hydrocarbon group having 1to 4 carbon atoms, more preferably —CH₂—, —(CH₂)₂—, —(CH₂)₃— and—(CH₂)₄—. Of these, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— and the like arepreferable.

In the formulas (I), (Ia) and (II), when Y is a group represented by theformula: —OR³ (R³ is as defined above), W and Wa are particularlypreferably —(CH₂)₃—.

In the formulas (I), (Ia) and (II), when Y is an optionally esterifiedor amidated carboxyl group, W and Wa are particularly preferably—(CH₂)₂—.

(4) Definition of Y

In the formulas (I), (Ia) and (II), Y is a group represented by theformula: —OR³ (R³ is hydrogen atom, optionally substituted hydrocarbongroup, optionally substituted heterocyclic group or optionallysubstituted acyl group) or optionally esterified or amidated carboxylgroup.

As used herein, the “optionally substituted heterocyclic group” and“optionally substituted acyl group” represented by R³ are eachexemplified by those exemplified as the “substituent” of the “optionallysubstituted cyclic group” represented by R¹ or R².

As used herein, the “optionally substituted hydrocarbon group”represented by R³ is exemplified by the “optionally substitutedaliphatic hydrocarbon group”, “optionally substituted alicyclichydrocarbon group” and “optionally substituted aromatic hydrocarbongroup” exemplified as the “substituent” of the “optionally substitutedcyclic group” represented by R¹ or R².

R³ is preferably a hydrogen atom, an alkyl group having 1 to 10 carbonatoms and the like, particularly preferably a hydrogen atom.

The “optionally esterified or amidated carboxyl group” represented by Yis exemplified by those exemplified as the “substituent” of the“optionally substituted cyclic group” represented by R¹ or R².

Specific examples of the “optionally esterified or amidated carboxylgroup” include

1) carboxyl group;

2) alkoxycarbonyl group having 2 to 5 carbon atoms (e.g.,methoxycarbonyl, ethoxycarbonyl and the like);

3) carbamoyl group (e.g., carbamoyl, ethylcarbamoyl,indolylethylcarbamoyl, methylpyrazylmethylcarbamoyl and the like)optionally mono- or di-substituted by C₁₋₆ alkyl group optionally having1 or 2 heterocyclic groups optionally substituted by C₁₋₆ alkyl group;

4) C₆₋₁₀ aryl-carbamoyl group (e.g.,diethylphosphonomethylphenylcarbamoyl, methoxycarbonylphenylcarbamoyl,carbamoylphenylcarbamoyl, ethoxycarbonylmethylphenylcarbamoyl,imidazolylphenylcarbamoyl, morpholinophenylcarbamoyl,ethyltriazolylethoxyphenylcarbamoyl and the like) optionally having 1 or2 substituents selected from (mono- or di-C₁₋₆ alkyl)-phosphono-C₁₋₆alkyl group; C₂₋₅ alkoxycarbonyl group; carbamoyl group; C₂-salkoxycarbonyl-C₁₋₆ alkyl group; heterocyclic group; and heterocyclicC₁₋₆ alkoxy group optionally substituted by C₁₋₆ alkyl group;

5) C₇₋₁₃ aralkyl-carbamoyl group (e.g., trifluoromethylbenzylcarbamoyl,methoxyphenylethylcarbamoyl and the like) optionally having 1 or 2substituents selected from C₁₋₆ alkyl group optionally substituted by 1to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike) and C₁₋₆ alkoxy-C₇₋₁₃ aralkyl group;

6) heterocyclic carbamoyl group (e.g.,4-(4-chlorophenyl)thiazol-2-yl-carbamoyl,5-methyl-3-phenylthiazol-2-yl-carbamoyl, quinolylcarbamoyl,pyridylcarbamoyl, (2-methyl-1-imidazolyl)pyridylcarbamoyl,pyrazylcarbamoyl, morpholinopyridylcarbamoyl and the like) optionallyhaving 1 or 2 substituents selected from C₆₋₁₀ aryl group optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like); C₁₋₆ alkyl; and heterocyclic group optionallysubstituted by C₁₋₆ alkyl;

7) C₇₋₁₄ aralkyl-nitrogen-containing (preferably saturated) heterocycliccarbonyl group (e.g., 4-diphenylmethylpiperazin-1-ylcarbonyl and thelike); and the like.

Of these, carboxyl group, alkoxycarbonyl group having 2 to 5 carbonatoms (e.g., methoxycarbonyl, ethoxycarbonyl and the like) and the likeare preferable.

Y is preferably an “optionally amidated carboxyl group”, more preferablyan “amidated carboxyl group” of the following a) to g) and the like.

a) Carbamoyl group optionally mono- or di-substituted by C₁₋₆ aliphatichydrocarbon group [e.g., alkyl group (e.g., methyl, ethyl, propyl,butyl, tert-butyl, 1-ethylpropyl, 2,2-dimethylpropyl and the like), C₂₋₆alkynyl group (e.g., propynyl and the like)] optionally having 1 or 2substituents selected from C₁₋₆ alkoxy group (e.g., methoxy, isopropoxyand the like); heterocyclic group (e.g., indolyl, imidazolyl, pyridyl,morpholino, furyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl and the like) optionally substituted by C₁₋₆ alkyl group(e.g., methyl and the like) or oxo group; C₁₋₆ alkylthio group (e.g.,methylthio and the like); mono- or di-C₁₋₆ alkylamino group (e.g.,dimethylamino, diethylamino, ethylmethylamino, diisopropylamino,N-methyl-N-phenylamino, di-hydroxyethyl-amino and the like) optionallysubstituted by hydroxy group, C₆₋₁₀ aryl group (e.g., phenyl and thelike) or C₁₋₆ alkyl-C₆₋₁₀ aryl group (e.g., methylphenyl and the like);C₆₋₁₀ arylamino group (e.g., phenylamino and the like); aromaticheterocyclic amino group (e.g., pyridylamino and the like) optionallysubstituted by nitro group; mono- or di-C₁₋₆ alkyl-phosphono group(e.g., diethylphosphono and the like).

b) C₆₋₁₄ Aryl-carbamoyl group (e.g., phenylcarbamoyl, naphthylcarbamoyl,dihydroindenylcarbamoyl, biphenylylcarbamoyl) optionally condensed withC₃₋₁₀ cycloalkane (e.g., cyclopentane) and optionally having 1 or 2substituents selected from halogen atom (e.g., fluorine, chlorine,bromine, iodine and the like); C₁₋₆ alkyl group (e.g., methyl,trifluoromethyl) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like); C₁₋₆ alkoxy group(e.g., methoxy, trifluoromethoxy) optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like);carbamoyl group; (mono- or di-C₁₋₆ alkyl-phosphono optionally forming aring)-C₁₋₆ alkyl group [e.g., methylphosphonomethyl,ethylphosphonomethyl, dimethylphosphonomethyl, diethylphosphonomethyl,ethylmethylphosphonomethyl, diisopropylphosphonomethyl,dibutylphosphonomethyl, diethylphosphonoethyl,(2-oxide-1,3,2-dioxaphosphinanyl)methyl,(methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(dimethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(diethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-ethyl-5-methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl and the like];phosphono-C₁₋₆ alkyl group (e.g., phosphonomethyl and the like); C₂₋₅alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and thelike); C₂₋₅ alkoxycarbonyl-C₁₋₆ alkyl group (e.g., ethoxycarbonylmethyland the like); heterocyclic group (e.g., imidazolyl, morpholino);heterocyclic C₁₋₆ alkoxy group (e.g., triazolylethoxy) optionallysubstituted by C₁₋₆ alkyl group (e.g., methyl, ethyl); C₁₋₃alkylenedioxy group (e.g., methylenedioxy, ethylenedioxy and the like);C₇₋₁₄ aralkyl group (e.g., benzyl); C₆₋₁₀ aryloxy group (e.g., phenoxyand the like); mono- or di-C₁₋₆ alkyl-phosphono group (e.g.,diethylphosphono and the like); mono- or di-(mono- or di-C₁₋₆alkyl-phosphono)-C₂₋₆ alkenyl group [e.g., bis(diethylphosphono)ethenyl,2-diethylphosphono-2-ethoxycarbonylethenyl and the like] optionallysubstituted by C₂₋₅ alkoxycarbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl and the like).

c) C₃₋₁₀ Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl,cyclohexylcarbamoyl, dihydroindenylcarbamoyl) optionally substituted by1 or 2 C₁₋₆ alkyl groups (e.g., methyl) and optionally condensed withbenzene ring.

d) C₇₋₁₃ Aralkyl-carbamoyl group (e.g., benzylcarbamoyl,phenethylcarbamoyl, phenylpropylcarbamoyl, benzhydrylcarbamoyl)optionally having 1 or 2 substituents selected from C₁₋₆ alkyl group(e.g., methyl, trifluoromethyl, dimethylaminoethyl, diethylaminoethyl)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) or mono- or di-C₁₋₆ alkylamino;C₁₋₆ alkoxy group (e.g., methoxy); C₁₋₃ alkylenedioxy group (e.g.,methylenedioxy and the like); C₆₋₁₄ aryl group (e.g., phenyl); and C₂₋₅alkoxycarbonyl-C₁₋₆ alkyl group (e.g., ethoxycarbonylethyl).

e) C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-carbamoyl group (e.g.,cyclohexylmethylcarbamoyl).

f) Heterocyclic carbamoyl group (e.g., piperidinylcarbamoyl,azepanylcarbamoyl, pyrrolidinylcarbamoyl, oxazolylcarbamoyl,thiazolylcarbamoyl, pyridylcarbamoyl, triazinylcarbamoyl,quinolylcarbamoyl, isoquinolylcarbamoyl, benzothiazolylcarbamoyl,pyrazolylcarbamoyl, piperazinylcarbamoyl, benzothiadiazolylcarbamoyl,pyrazinylcarbamoyl) optionally having 1 to 4 (preferably 1 or 2)substituents selected from C₆₋₁₀ aryl group (e.g., phenyl and the like)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like); C₁₋₆ alkyl (e.g., methyl)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like); heterocyclic group (e.g.,imidazolyl, morpholino) optionally substituted by C₁₋₆ alkyl group(e.g., methyl); C₇₋₁₄ aralkyl group (e.g., benzyl); and oxo group.

g) Nitrogen-containing heterocyclic carbonyl group (e.g.,piperidinylcarbonyl, pyrrolidinylcarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, piperazinylcarbonyl,tetrahydroisoquinolinecarbonyl, decahydroisoquinolinecarbonyl,azepanecarbonyl, azocanecarbonyl, 1,2,3,6-tetrahydropyridinecarbonyl andthe like) optionally condensed with benzene ring or C₃₋₁₀ cycloalkane(e.g., cyclohexane and the like), and optionally having 1 or 2substituents selected from C₁₋₆ alkyl (e.g., methyl, ethyl and the like)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), hydroxy group, C₂₋₇alkoxycarbonyl group (e.g., ethoxycarbonyl) or 5 or 6-memberednitrogen-containing heterocyclic group (e.g., pyrrolidinyl and thelike); C₇₋₁₄ aralkyl group (e.g., benzyl, benzhydryl and the like)optionally substituted by C₁₋₃ alkylenedioxy group (e.g., methylenedioxyand the like); C₆₋₁₄ aryl group (e.g., phenyl and the like) optionallysubstituted by C₁₋₆ alkyl group (e.g., methyl, trifluoromethyl and thelike) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy and the like) or C₂₋₁₀ alkanoyl group (e.g., acetyl andthe like); C₆₋₁₄ aryl-C₂₋₆ alkenyl group (e.g., phenylpropenyl and thelike); C₆₋₁₄ arylamino-C₁₋₆ alkyl group (e.g., phenylaminomethyl and thelike) optionally substituted by C₁₋₆ alkyl group (e.g., methyl and thelike); cyano group; oxo group; hydroxy group; mono- or di-C₂₋₁₀alkanoylamino group (e.g., acetylamino, trifluoroacetylamino,propionylamino, N-acetyl-N-ethylamino and the like) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like) or C₁₋₆ alkyl group (e.g., methyl, ethyl and thelike); C₂₋₇ alkoxycarbonylamino group (e.g., tert-butoxycarbonylaminoand the like); 5 or 6-membered nitrogen-containing heterocyclic group(e.g., pyridyl, piperidinyl, pyrimidinyl, pyrrolidinyl and the like);aromatic heterocyclic carbonyl group (e.g., furoyl and the like);carbamoyl group; C₂₋₁₀ alkanoyl group (e.g., acetyl and the like); andC₂₋₇ alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and thelike).

Of these, b), d) and f) are preferable. Particularly, C₆₋₁₄aryl-carbamoyl group (preferably phenylcarbamoyl) optionally substitutedby (mono- or di-C₁₋₆ alkyl-phosphono optionally forming a ring)-C₁₋₆alkyl group [e.g., dimethylphosphonomethyl, diethylphosphonomethyl,diisopropylphosphonomethyl, dibutylphosphonomethyl,diethylphosphonoethyl, (2-oxide-1,3,2-dioxaphosphinanyl)methyl,(methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(dimethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(diethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-ethyl-5-methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl and the like]is preferable.

(5) Preferable Compound

Of the compounds represented by the formula (I) and a salt thereof, acompound represented by the formula (II) (except5-phenyl-4-isoxazolylmethanol and 5-phenyl-4-isoxazolylacetic acid) anda salt thereof are novel compounds.

Preferable examples of a compound represented by the formula (II)include the following compounds (A), (B), (C) and the like.

Compound (A)

A compound wherein

R^(1a) is a hydrogen atom;

R^(2a) is an aromatic hydrocarbon group (preferably phenyl, naphthyl) oraromatic heterocyclic group (preferably furyl, thienyl, pyridyl,quinolyl, more preferably thienyl, pyridyl) optionally having 1 to 3substituents selected from

1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine);

2) an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl,trifluoromethyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

3) an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy,trifluoromethoxy) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

4) an alkylthio group having 1 to 6 carbon atoms (e.g., methylthio)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine);

5) a nitro group;

6) a cyano group;

7) a C₁₋₃ alkylenedioxy group (e.g., methylenedioxy);

8) an aryl group having 6 to 14 carbon atoms (e.g., phenyl);

9) an alkylsulfinyl group having 1 to 6 carbon atoms (e.g.,methylsulfinyl); and

10) alkylsulfonyl group having 1 to 6 carbon atoms (e.g.,methylsulfonyl);

Wa is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms(preferably —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—; more preferably—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—; particularly preferably —(CH₂)₃—);

Y is a group represented by the formula: —OR³, and

R³ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.

Compound (B)

A compound wherein

R^(1a) is a hydrogen atom;

R^(2a) is an aromatic hydrocarbon group (preferably phenyl, naphthyl) oraromatic heterocyclic group (preferably furyl, thienyl, pyridyl,quinolyl, more preferably thienyl, pyridyl) optionally having 1 to 3substituents selected from

1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine);

2) an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl,trifluoromethyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

3) an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy,trifluoromethoxy) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

4) an alkylthio group having 1 to 6 carbon atoms (e.g., methylthio)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine);

5) a nitro group;

6) a cyano group;

7) a C₁₋₃ alkylenedioxy group (e.g., methylenedioxy);

8) an aryl group having 6 to 14 carbon atoms (e.g., phenyl);

9) an alkylsulfinyl group having 1 to 6 carbon atoms (e.g.,methylsulfinyl); and

10) an alkylsulfonyl group having 1 to 6 carbon atoms (e.g.,methylsulfonyl);

Wa is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms(preferably —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—; more preferably—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—; particularly preferably —(CH₂)₂—); and

Y is a carboxyl group or alkoxycarbonyl group having 2 to 5 carbon atoms(e.g., methoxycarbonyl, ethoxycarbonyl and the like).

Compound (C)

A compound wherein

R^(1a) is a hydrogen atom;

R^(2a) is an aromatic hydrocarbon group (preferably phenyl, naphthyl) oraromatic heterocyclic group (preferably furyl, thienyl, pyridyl,quinolyl, more preferably thienyl, pyridyl) optionally having 1 to 3substituents selected from

1) a halogen atom (e.g., fluorine, chlorine, bromine, iodine);

2) an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl,trifluoromethyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

3) an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy,trifluoromethoxy) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine);

4) an alkylthio group having 1 to 6 carbon atoms (e.g., methylthio)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine);

5) a nitro group;

6) a cyano group;

7) a C₁₋₃ alkylenedioxy group (e.g., methylenedioxy);

8) an aryl group having 6 to 14 carbon atoms (e.g., phenyl);

9) an alkylsulfinyl group having 1 to 6 carbon atoms (e.g.,methylsulfinyl); and

10) an alkylsulfonyl group having 1 to 6 carbon atoms (e.g.,methylsulfonyl);

Wa is a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms(preferably —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—; more preferably—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—; particularly preferably —(CH₂)₂—);

Y is a) carbamoyl group optionally mono- or di-substituted by C₁₋₆aliphatic hydrocarbon group [e.g., alkyl group (e.g., methyl, ethyl,propyl, butyl, tert-butyl, 1-ethylpropyl, 2,2-dimethylpropyl and thelike), C₂₋₆ alkynyl group (e.g., propynyl and the like)] optionallyhaving 1 or 2 substituents selected from C₁₋₆ alkoxy group (e.g.,methoxy, isopropoxy and the like); heterocyclic group (e.g., indolyl,imidazolyl, pyridyl, morpholino, furyl, tetrahydrofuranyl, pyrrolidinyl,piperidinyl, piperazinyl and the like) optionally substituted by C₁₋₆alkyl group (e.g., methyl and the like) or oxo group; C₁₋₆ alkylthiogroup (e.g., methylthio and the like); mono- or di-C₁₋₆ alkylamino group(e.g., dimethylamino, diethylamino, ethylmethylamino, diisopropylamino,N-methyl-N-phenylamino, di-hydroxyethyl-amino and the like) optionallysubstituted by hydroxy group, C₆₋₁₀ aryl group (e.g., phenyl and thelike) or C₁₋₆ alkyl-C₆₋₁₀ aryl group (e.g., methylphenyl and the like);C₆₋₁₀ arylamino group (e.g., phenylamino and the like); aromaticheterocyclic amino group (e.g., pyridylamino and the like) optionallysubstituted by nitro group; mono- or di-C₁₋₆ alkyl-phosphono group(e.g., diethylphosphono and the like);

b) C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl, naphthylcarbamoyl,dihydroindenylcarbamoyl, biphenylylcarbamoyl) optionally condensed withC₃₋₁₀ cycloalkane (e.g., cyclopentane) and optionally having 1 or 2substituents selected from halogen atom (e.g., fluorine, chlorine,bromine, iodine and the like); C₁₋₆ alkyl group (e.g., methyl,trifluoromethyl) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like); C₁₋₆ alkoxy group(e.g., methoxy, trifluoromethoxy) optionally substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like);carbamoyl group; (mono- or di-C₁₋₆ alkyl-phosphono optionally forming aring)-C₁₋₆ alkyl group [e.g., methylphosphonomethyl,ethylphosphonomethyl, dimethylphosphonomethyl, diethylphosphonomethyl,ethylmethylphosphonomethyl, diisopropylphosphonomethyl,dibutylphosphonomethyl, diethylphosphonoethyl,(2-oxide-1,3,2-dioxaphosphinanyl)methyl,(methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(dimethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(diethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl,(5-ethyl-5-methyl-2-oxide-1,3,2-dioxaphosphinanyl)methyl and the like];C₂₋₅ alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and thelike); C₂₋₅ alkoxycarbonyl-C₁₋₆ alkyl group (e.g., ethoxycarbonylmethyland the like); phosphono-C₁₋₆ alkyl group (e.g., phosphonomethyl and thelike); heterocyclic group (e.g., imidazolyl, morpholino);heterocyclic-C₁₋₆ alkoxy group (e.g., triazolylethoxy) optionallysubstituted by C₁₋₆ alkyl group (e.g., methyl, ethyl); C₁₋₃alkylenedioxy group (e.g., methylenedioxy, ethylenedioxy and the like);C₇₋₁₄ aralkyl group (e.g., benzyl); C₆₋₁₀ aryloxy group (e.g., phenoxyand the like); mono- or di-C₁₋₆ alkyl-phosphono group (e.g.,diethylphosphono and the like); and mono- or di-(mono- or di-C₁₋₆alkyl-phosphono)-C₂₋₆ alkenyl group [e.g., bis(diethylphosphono)ethenyl,2-diethylphosphono-2-ethoxycarbonylethenyl and the like] optionallysubstituted by C₂₋₅ alkoxycarbonyl group (e.g., methoxycarbonyl,ethoxycarbonyl and the like);

c) C₃₋₁₀ cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl,cyclohexylcarbamoyl, dihydroindenylcarbamoyl) optionally substituted by1 or 2 C₁₋₆ alkyl groups (e.g., methyl) and optionally condensed with abenzene ring;

d) C₇₋₁₃ aralkyl-carbamoyl group (e.g., benzylcarbamoyl,phenethylcarbamoyl, phenylpropylcarbamoyl, benzhydrylcarbamoyl)optionally having 1 or 2 substituents selected from C₁₋₆ alkyl group(e.g., methyl, trifluoromethyl, dimethylaminoethyl, diethylaminoethyl)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like) or mono- or di-C₁₋₆ alkylamino;C₁₋₆ alkoxy group (e.g., methoxy); C₁₋₃ alkylenedioxy group (e.g.,methylenedioxy and the like); C₆₋₁₄ aryl group (e.g., phenyl); and C₂₋₅alkoxycarbonyl-C₁₋₆ alkyl group (e.g., ethoxycarbonylethyl);

e) C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-carbamoyl group (e.g.,cyclohexylmethylcarbamoyl);

f) heterocyclic carbamoyl group (e.g., piperidinylcarbamoyl,azepanylcarbamoyl, pyrrolidinylcarbamoyl, oxazolylcarbamoyl,thiazolylcarbamoyl, pyridylcarbamoyl, triazinylcarbamoyl,quinolylcarbamoyl, isoquinolylcarbamoyl, benzothiazolylcarbamoyl,pyrazolylcarbamoyl, piperazinylcarbamoyl, benzothiadiazolylcarbamoyl,pyrazinylcarbamoyl) optionally having 1 to 4 (preferably 1 or 2)substituents selected from C₆₋₁₀ aryl group (e.g., phenyl and the like)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like); C₁₋₆ alkyl (e.g., methyl)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like); heterocyclic group (e.g.,imidazolyl, morpholino) optionally substituted by C₁₋₆ alkyl group(e.g., methyl); C₇₋₁₄ aralkyl group (e.g., benzyl); and oxo group; or

g) a nitrogen-containing heterocyclic carbonyl group (e.g.,piperidinylcarbonyl, pyrrolidinylcarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, piperazinylcarbonyl,tetrahydroisoquinolinecarbonyl, decahydroisoquinolinecarbonyl,azepanecarbonyl, azocanecarbonyl, 1,2,3,6-tetrahydropyridinecarbonyl andthe like) optionally condensed with benzene ring or C₃₋₁₀ cycloalkane(e.g., cyclohexane and the like), and optionally having 1 or 2substituents selected from C₁₋₆ alkyl (e.g., methyl, ethyl and the like)optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), hydroxy group, C₂₋₇alkoxycarbonyl group (e.g., ethoxycarbonyl) or 5 or 6-memberednitrogen-containing heterocyclic group (e.g., pyrrolidinyl and thelike); C₇₋₁₄ aralkyl group (e.g., benzyl, benzhydryl and the like)optionally substituted by C₁₋₃ alkylenedioxy group (e.g., methylenedioxyand the like); C₆₋₁₄ aryl group (e.g., phenyl and the like) optionallysubstituted by C₁₋₆ alkyl group (e.g., methyl, trifluoromethyl and thelike) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy and the like) or C₂₋₁₀ alkanoyl group (e.g., acetyl andthe like); C₆₋₁₄ aryl-C₂₋₆ alkenyl group (e.g., phenylpropenyl and thelike); C₆₋₁₄ arylamino-C₁₋₆ alkyl group (e.g., phenylaminomethyl and thelike) optionally substituted by C₁₋₆ alkyl group (e.g., methyl and thelike); cyano group; oxo group; hydroxy group; mono- or di-C₂₋₁₀alkanoylamino group (e.g., acetylamino, trifluoroacetylamino,propionylamino, N-acetyl-N-ethylamino and the like) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine and the like) or C₁₋₆ alkyl group (e.g., methyl, ethyl and thelike); C₂₋₇ alkoxycarbonylamino group (e.g., tert-butoxycarbonylaminoand the like); 5 or 6-membered nitrogen-containing heterocyclic group(e.g., pyridyl, piperidinyl, pyrimidinyl, pyrrolidinyl and the like);aromatic heterocyclic carbonyl group (e.g., furoyl and the like);carbamoyl group; C₂₋₁₀ alkanoyl group (e.g., acetyl and the like); C₂₋₇alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and thelike).

Of the aforementioned compounds (A), (B) and (C), the followingcompounds and the like are preferable:

-   3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol;-   3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid;-   3-[5-(4-chlorophenyl)-4-isoxazolyl]propan-1-ol;-   3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid;-   3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propan-1-ol;-   3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionic acid;-   N-[4-(diethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide;-   N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide;-   N-[4-(dimethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide;-   N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-(5-phenyl-4-isoxazolyl)propionamide;-   N-benzyl-N-[2-(dimethylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide;    and-   N-benzyl-N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide.    (6) Salt

The salt of compound represented by the formula (I), (Ia) or (II)(hereinafter sometimes to be abbreviated as compound (I), (Ia) or (II))is preferably a pharmacologically acceptable one and may be, forexample, a salt with an inorganic base, a salt with an organic base, asalt with an inorganic acid, a salt with an organic acid or a salt witha basic or acidic amino acid. Preferable examples of the salt with aninorganic base include alkali metal salts such as sodium salt andpotassium salt; alkaline earth metal salts such as calcium salt andmagnesium salt; and aluminum salt, ammonium salt and the like.Preferable examples of the salt with an organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, and the like. Preferable examples of thesalt with an inorganic acid include salts with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.Preferable examples of the salt with an organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, and the like. Preferable examples of the salt with a basic aminoacid include salts with arginine, lysine and ornithine. Preferableexamples of the salt with an acidic amino acid include salts withaspartic acid, glutamic acid, and the like. Among these salts, a sodiumsalt and potassium salt are most preferred.

(7) Prodrug and the Like

The “prodrug of compound (I) means a compound that can be converted tocompound (I) in vivo by the action of an enzyme or gastric juice underphysiological conditions, namely a compound capable of being convertedto compound (I) upon enzymatic oxidation, reduction or hydrolysis, amongothers, or a compound capable of being converted to compound (I) uponhydrolysis by gastric juice. The prodrug of compound (I) includescompounds derived by acylation, alkylation or phosphorylation of theamino group of compound (I) (e.g., compounds derived by eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation of the amino group of compound (I)), compounds derivedby acylation, alkylation, phosphorylation or boration of the hydroxygroup of compound (I) (e.g., compounds derived by acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation or dimethylaminomethylcarbonylation of thehydroxy group of compound (I)), and compounds derived by esterificationor amidation of the carboxyl group of compound (I) (e.g., compoundsderived by ethyl esterification, phenyl esterification, carboxymethylesterification, dimethylaminomethyl esterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethyl esterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification, or methylamidation of thecarboxyl group of compound (I)), among others. These compounds can beproduced from compound (I) by a method known per se.

The prodrug of compound (I) may be one that can be converted to compound(I) under physiological conditions, as described in “Iyakuhin noKaihatsu (Development of Drugs)”, vol 7, Molecular Designing, publishedby Hirokawa Shoten, 1990, pages 163-198.

As the prodrug of compound (Ia) or (II), those similar to the prodrug ofthe aforementioned compound (I) are exemplified.

The compounds (I), (Ia) and compound (II) may be labeled with isotope(e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and the like) and the like.

The compounds (I), (Ia) and compound (II) may be an anhydride or ahydrate.

(8) Formulation

The compounds (I), (Ia), (II) and a salt thereof (hereinafter sometimesto be simply referred to as the compound of the present invention) showlow toxicity and can be used, as they are or by admixing with apharmacologically acceptable carrier and the like to give apharmaceutical composition, as agents for the prophylaxis or treatmentof various diseases to be mentioned later for mammals (e.g., human,mouse, rat, rabbit, dog, cat, cattle, horse, swine, simian and thelike).

The above-mentioned pharmacologically acceptable carrier includesvarious organic or inorganic carrier substances which are conventionallyused as pharmaceutical preparation materials. They are incorporated asexcipients, lubricants, binders, disintegrants or the like in solidpreparations; as solvents, solubilizers, suspending agents, isotonizingagents, buffers, analgesics or the like in liquid preparations. Wherenecessary, additives such as preservatives, antioxidants, coloringagents and sweeteners may be used.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose,carboxymethylcellulose sodium, gum arabic, dextrin, pullulan, lightsilicic anhydride, synthetic aluminum silicate, magnesiumaluminometasilicate and the like.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinized starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose,carboxymethylcellulose sodium, crystalline cellulose, saccharose,D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, carboxymethylcellulose calcium,croscarmellose sodium, carboxymethylstarch sodium, light silicicanhydride and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological saline, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizer include polyethylene glycol,propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride andglycerol monostearate; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcellulose; polysorbates, polyoxyethylene-hardened castoroil, and so forth.

Preferable examples of the isotonizing agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffer solutions of phosphate,acetate, carbonate and citrate.

Preferable examples of the local analgesic include benzyl alcohol andthe like.

Preferable examples of the preservative include para-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the anti-oxidant include sulfite salts andascorbate salts.

Preferable examples of the coloring agent include water-soluble edibletar colors (e.g., food colors such as Food Color Red No. 2 and No. 3,Food Color Yellow No. 4 and No. 5, Food Color Blue No. 1 and No. 2),water-insoluble lake colors (e.g., the aluminum salt form of the abovewater-soluble edible tar colors), and natural colors (e.g., β-carotene,chlorophyll, iron oxide red).

Preferred examples of the sweeteners include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

(9) Mode of Administration

The dosage form of the above-mentioned pharmaceutical compositionincludes, for example, oral preparations such as tablets, capsules(including soft capsules and microcapsules), granules, powders, syrups,emulsions and suspensions; non-oral preparations such as injections(e.g., subcutaneous injection, intravenous injection, intramuscularinjection, intraperitoneal injection), external application forms (e.g.,nasal preparations, transdermal preparations, ointments), suppositories(e.g., rectal suppositories, vaginal suppositories), pellets, solutionsfor instillation, sustained-release preparations (e.g.,sustained-release microcapsule) and the like. These can be each safelyadministered orally or non-orally.

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical preparations, such asthe method described in Japan Pharmacopoeia and the like. The specificproduction methods of the pharmaceutical preparation are described indetail in the following. While the content of the compound of thepresent invention in the pharmaceutical composition varies depending onthe dosage form, dose of the compound of the present invention and thelike, it is, for example, about 0.1-100 wt %.

For example, an oral agent is produced by adding, to the activeingredient, an excipient (e.g., lactose, sucrose, starch, D-mannitol andthe like), a disintegrant (e.g., carboxymethylcellulose calcium and thelike), a binder (e.g., gelatinized starch, gum arabic,carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone andthe like), a lubricant (e.g., talc, magnesium stearate, polyethyleneglycol 6000 and the like) and the like, compression-molding the mixture,and where necessary, coating the same using a coating base for maskingof taste, enteric property or sustained release according to a methodknown per se.

Examples of the coating base include a sugar coating base, awater-soluble film coating base, an enteric film coating base, or asustained-release film coating base and the like.

Useful as the sugar coating base is sucrose and, further, one or moreingredients selected from talc, precipitated calcium carbonate, gelatin,gum arabic, pullulan, carnauba wax and the like may be used incombination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose and methylhydroxyethylcellulose; syntheticpolymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trademark), Rohm Pharma] andpolyvinylpyrrolidone; and polysaccharides such as pullulan and the like;and the like.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, and cellulose acetate phthalate; acrylicacid polymers such as methacrylic acid copolymer L [Eudragit L(trademark), Rohm Pharma], methacrylic acid copolymer LD [EudragitL-30D55 (trademark), Rohm Pharma] and methacrylic acid copolymer S[Eudragit S (trademark), Rohm Pharma]; and natural products such asshellac and the like.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose; acrylic acid polymers such asaminoalkyl methacrylate copolymer RS [Eudragit RS (trademark), RohmPharma] and an ethyl acrylate-methyl methacrylate copolymer suspension[Eudragit NE (trademark), Rohm Pharma]; and so forth.

Two or more of the above coating bases may be used in admixture inappropriate proportions. On the occasion of coating, a shading agentsuch as titanium oxide, red ferric oxide may be used.

Injections are produced by dissolving, suspending or emulsifying theactive ingredient in an aqueous solvent (e.g., distilled water,physiological saline, Ringer's solution) or an oleaginous solvent (e.g.,vegetable oils such as olive oil, sesame oil, cotton seed oil, corn oil;propylene glycol), together with a dispersant (e.g., polysorbate 80,polyoxyethylene-hardened castor oil 60, polyethylene glycol,carboxymethylcellulose, sodium alginate), a preservative (e.g.,methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol), anisotonizing agent (e.g., sodium chloride, glycerol, D-mannitol,D-sorbitol, glucose) and the like. If desirable, additives such as asolubilizer (e.g., sodium salicylate, sodium acetate), a stabilizer(e.g., human serum albumin), an analgesic (e.g., benzyl alcohol), may beused.

(10) Target Disease

The compound of the present invention and the pharmaceutical agent ofthe present invention are useful as agents for prophylaxis or treatmentof diabetes (e.g., type 1 diabetes, type 2 diabetes, gestationaldiabetes and the like); agents for prophylaxis or treatment ofhyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, lowHDL lipemia, postprandial hyperlipemia and the like); agents forprophylaxis or treatment of arteriosclerosis; agents for prophylaxis ortreatment of impaired glucose tolerance [IGT (Impaired GlucoseTolerance)]; an insulin secretagogue; and an agent for suppressingprogress of impaired glucose tolerance into diabetes.

For diagnostic criteria of diabetes, Japan Diabetes Society reported newdiagnostic criteria in 1999.

According to this report, diabetes is a condition showing any of afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test(75 g OGTT) 2 h level (glucose concentration of intravenous plasma) ofnot less than 200 mg/dl, a non-fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 200 mg/dl. Acondition not falling under the above-mentioned diabetes, and not being“a condition showing a fasting blood glucose level (glucoseconcentration of intravenous plasma) of less than 110 mg/dl or a 75 goral glucose tolerance test (75 g OGTT) 2 h level (glucose concentrationof intravenous plasma) of less than 140 mg/dl” (normal type) is called a“borderline type”.

In addition, ADA (American Diabetes Association) reported new diagnosticcriteria of diabetes in 1997 and WHO in 1998.

According to these reports, diabetes is a condition showing a fastingblood glucose level (glucose concentration of intravenous plasma) of notless than 126 mg/dl and a 75 g oral glucose tolerance test 2 hr level(glucose concentration of intravenous plasma) of not less than 200mg/dl.

According to the above-mentioned reports, impaired glucose tolerance isa condition showing a fasting blood glucose level (glucose concentrationof intravenous plasma) of less than 126 mg/dl and a 75 g oral glucosetolerance test 2 hr level (glucose concentration of intravenous plasma)of not less than 140 mg/dl and less than 200 mg/dl. According to thereport of ADA, a condition showing a fasting blood glucose level(glucose concentration of intravenous plasma) of not less than 110 mg/dland less than 126 mg/dl is called IFG (Impaired Fasting Glucose).According to the report of WHO, among the IFG (Impaired FastingGlucose), a condition showing a 75 g oral glucose tolerance test 2 hrlevel (glucose concentration of intravenous plasma) of less than 140mg/dl is called IFG (Impaired Fasting Glycemia).

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used as agents for prophylaxis ortreatment of diabetes, borderline type, impaired glucose tolerance, IFG(Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia), asdetermined according to the above-mentioned new diagnostic criteria.Moreover, the compound of the present invention and the pharmaceuticalagent of the present invention can prevent progress of borderline type,impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG(Impaired Fasting Glycemia) into diabetes.

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used as agents for prophylaxis ortreatment of, for example, diabetic complications [e.g., neuropathy,nephropathy, retinopathy, cataract, macroangiopathy, osteopenia,hyperosmolar diabetic coma, infectious disease (respiratory infection,urinary tract infection, gastrointestinal infection, dermal soft tissueinfections, inferior limb infection and the like), diabetic gangrene,xerostomia, hypacusis, cerebrovascular disorder, peripheral bloodcirculation disorder and the like], obesity, osteoporosis, cachexia(e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia,blood disease cachexia, endocrine disease cachexia, infectious diseasecachexia or cachexia due to acquired immunodeficiency syndrome), fattyliver, hypertension, polycystic ovary syndrome, kidney disease (e.g.,diabetic nephropathy, glomerular nephritis, glomerulosclerosis,nephrotic syndrome, hypertensive nephrosclerosis, end stage kidneydisease and the like), muscular dystrophy, myocardial infarction, anginapectoris, cerebrovascular accident (e.g., cerebral infarction, cerebralapoplexy), insulin resistance syndrome, Syndrome X, hyperinsulinemia,hyperinsulinemia-induced sensory disorder, tumor (e.g., leukemia, breastcancer, prostatic cancer, skin cancer and the like), irritable bowelsyndrome, acute or chronic diarrhea, inflammatory diseases (e.g.,chronic rheumatoid arthritis, spondylitis deformans, arthritiscleformans, lumbar pain, gout, postoperative or traumatic inflammation,remission of tumentia, neuralgia, pharyngolaryngitis, cystitis,hepatitis (inclusive of nonalcoholic steatohepatitis), pneumonia,pancreatitis, inflammatory bowel disease, ulcerative colitis, gastricmucosal injury (inclusive of gastric mucosal injury caused by aspirin)and the like), visceral obesity syndrome and the like.

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used for decreasing visceral fat,suppressing visceral fat accumulation, improving glycometabolism,improving lipid metabolism, suppressing production of oxidized LDL,improving lipoprotein metabolism, improving coronary artery metabolism,prophylaxis or treatment of cardiovascular complications, prophylaxis ortreatment of heart failure complications, lowering blood remnant,prophylaxis or treatment of anovulation, prophylaxis or treatment ofhypertrichosis, prophylaxis or treatment of hyperandrogenemia and thelike.

The compound of the present invention and the pharmaceutical agent ofthe present invention can be also used for secondary prophylaxis orsuppression of progression of the above-mentioned various diseases(e.g., cardiovascular event such as myocardial infarction and the like).

Particularly, the compound of the present invention and thepharmaceutical agent of the present invention are useful glucosedependent insulin secretagogues that exhibit a selective insulinsecretion promoting action only in the presence of high concentrationglucose (e.g., in patients showing fasting blood glucose level of notless than 126 mg/dl or 75 g oral glucose tolerance test (75 g OGTT) 2 hlevel of not less than 140 mg/dl and the like). Therefore, the compoundof the present invention and the pharmaceutical agent of the presentinvention are particularly useful as safe agents for prophylaxis ortreatment of diabetes, which are associated with a low risk of vascularcomplications, induction of hypoglycemia and the like, which are thenegative effects caused by insulin.

While the dose of the compound of the present invention and thepharmaceutical agent of the present invention varies depending on theadministration subject, administration route, target disease, conditionand the like, the compound of the present invention as an activeingredient is generally given in a single dose of about 0.01-100 mg/kgbody weight, preferably 0.05-30 mg/kg body weight, more preferably 0.1-2mg/kg body weight, in the case of, for example, oral administration toadult diabetic patients. This dose is desirably given 1 to 3 times aday.

(11) Combined Use with Pharmaceutical Agent

The compound of the present invention can be used in combination withtherapeutic agents such as a therapeutic agent of diabetes, atherapeutic agent of diabetic complications, an antihyperlipemic agent,a hypotensive agent, an antiobesity agent, a diuretic agent, achemotherapeutic agent, an immunotherapeutic agent, an antithromboticagent, a therapeutic agent of osteoporosis, an antidementia agent, anagent for ameliorating erectile dysfunction, a therapeutic agent ofincontinentia or pollakiuria and the like (hereinafter to be brieflyreferred to as a combination drug). In this case, the timing ofadministration of the compound of the present invention and acombination drug is not limited. These may be simultaneouslyadministered to an administration subject or, administered in astaggered manner. The dose of the combination drug can be determined asappropriate based on the dose clinically employed. The proportion of thecompound of the present invention and combination drug can beappropriately determined depending on the administration subject,administration route, target disease, condition, combination and thelike. When, for example, the administration subject is human, acombination drug is used in an amount of 0.01-100 parts by weight per 1part by weight of the compound of the present invention.

Examples of the therapeutic agent of diabetes include insulinpreparations (e.g., animal insulin preparations obtained by extractionfrom the bovine or swine pancreas; human insulin preparationssynthesized by a genetic engineering technique using Escherichia coli ora yeast; insulin-zinc; protamine-insulin-zinc; fragment or derivative ofinsulin (e.g., INS-1 and the like)), insulin sensitizers (e.g.,pioglitazone hydrochloride, rosiglitazone or its maleate, GI-262570,JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614, the compoundsdescribed in WO99/58510 such as(E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid), NN-622, AR-H-039242, BMS-298585, EML-16336 and the like),α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol,emiglitate), biguanides (e.g., phenformin, metformin, buformin), insulinsecretagogue [sulfonylureas (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, glipizide, glybuzole etc.), repaglinide, senaglinide,nateglinide, mitiglinide or its calcium salt hydrate], GLP-1 receptoragonist [e.g., GLP-1, NN-2211, AC-2993 (exendin-4), BIM-51077,Aib(8,35)hGLP-[(7,37)NH₂ etc.], amyrin agonist (e.g., pramlintide),phosphotyrosine phosphatase inhibitors (e.g., vanadic acid),dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278, PT-100, P32/98),β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677,BMS-196085, AZ40140), gluconeogenesis inhibitors (e.g., glycogenphosphorylase inhibitors, glucose-6-phosphatse inhibitors, glucagonantagonists), SGLT (sodium-glucose cotransporter) inhibitors (e.g.,T-1095), etc.

Examples of the therapeutic agent of diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidarestat, SNK-860, CT-112), neurotrophicfactors and increasing agents thereof (e.g., NGF, NT-3, BDNF,neurotrophin production secretion promoter such as4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazoleetc.,) and the like, neuranagenesis promoters (e.g., Y-128 etc.), PKCinhibitors (e.g., LY-333531 etc.), AGE inhibitors (e.g., ALT-946,pimagedine, pyradoxamine, N-phenacylthiazolium bromide (ALT-766),EXO-226), active oxygen scavengers (e.g., thioctic acid), cerebralvasodilators (e.g., tiapoburide, mexiletine), and the like.

Examples of the antihyperlipemic agent include statin compounds whichare cholesterol synthesis inhibitors (e.g., pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin ortheir salts (e.g., sodium salt)), squalene synthase inhibitors (e.g.,the compounds described in WO97/10224, such asN-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-aceticacid etc.) or fibrate compounds (e.g., bezafibrate, clofibrate,simfibrate, clinofibrate) having a triglyceride lowering action, and thelike.

Examples of the hypotensive agent include angiotensin converting enzymeinhibitors (e.g., captopril, enalapril, delapril), angiotensin IIantagonists (e.g., candesartan cilexetil, losartan, eprosartan,balsartan, telmisartan, irbesartan, tasosartan), calcium antagonist(e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine),clonidine, and the like.

Examples of the antiobesity agent include antiobesity drugs acting onthe central nervous system (e.g., dexfenfluramine, fenfluramine,phentermine, sibutramine, anfepramon, dexamphetamine, mazindol,phenylpropanolamine, clobenzorex), pancreatic lipase inhibitors (e.g.,orlistat), 3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307,SB-226552, AJ-9677, BMS-196085, AZ40140), anorectic peptides (e.g.,leptin, CNTF (Ciliary Neurotrophic Factor)), cholecystokinin agonists(e.g., lintitript, FPL-15849), and the like.

Examples of the diuretic agent include xanthine derivatives (e.g.,theobromine and sodium salicylate, theobromine and calcium salicylate),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichlormethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide,methyclothiazide), antialdosterone preparations (e.g., spironolactone,triamterene), carbonate dehydratase inhibitors (e.g., acetazolamide),chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefruside,indapamide), azosemide, isosorbide, ethacrynic acid, piretanide,bumetanide, furosemide, and the like.

Examples of the chemotherapeutic agent include alkylating agents (e.g.,cyclophosphamide, ifosamide), metabolic antagonists (e.g., methotrexate,5-fluorouracil), antitumor antibiotics (e.g., mitomycin, adriamycin),plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol),cisplatin, carboplatin, etoposide, and the like. Among these,5-fluorouracil derivatives such as Furtulon and Neo-Furtulon arepreferable.

Examples of the immunotherapeutic agent include microorganism- orbacterium-derived components (e.g., muramyl dipeptide derivatives,Picibanil), immunopotentiator polysaccharides (e.g., lentinan,schizophyllan, krestin), genetically engineered cytokines (e.g.,interferons, interleukins (IL)), colony stimulating agents (e.g.,granulocyte colony stimulating factor, erythropoietin), and the like.Among these, IL-1, IL-2, IL-12 and the like are preferable.

Examples of the antithrombotic agent include heparin (e.g., heparinsodium, heparin calcium, dalteparin sodium and the like), warfarin(e.g., warfarin potassium and the like), anti-thrombin drugs (e.g.,aragatroban and the like), thrombolytic agents (e.g., urokinase,tisokinase, alteplase, nateplase, monteplase, pamiteplase and the like),platelet aggregation inhibitors (e.g., ticlopidine hydrochloride,cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelatehydrochloride and the like) and the like.

Examples of the therapeutic agent of osteoporosis include alfacalcidol,calcitriol, elcaltonin, calcitonin salmon, estriol, ipriflavone,pamidronate disodium, alendronate sodium hydrate, incadronate disodiumand the like.

Examples of the antidementia agent include tacrine, donepezil,rivastigmine, galantamine and the like.

Examples of the agent for ameliorating erectile dysfunction includeapomorphine, sildenafil citrate and the like.

Examples of the therapeutic agent of incontinentia or pollakiuriainclude flavoxate hydrochloride, oxybutynin hydrochloride, propiverinehydrochloride and the like.

Further, agents whose effects of ameliorating cachexia have beenconfirmed in animal models or clinically, namely cyclooxygenaseinhibitors (e.g., indomethacin) (Cancer Research, vol. 49, pp.5935-5939, 1989), progesterone derivatives (e.g., megestrol acetate)(Journal of Clinical Oncology, vol. 12, pp. 213-225, 1994),glucocorticoids (e.g., dexamethasone), metoclopramide pharmaceuticals,tetrahydrocannabinol pharmaceuticals (the above references are appliedto both), fat metabolism ameliorating agents (e.g., eicosapentanoicacid) (British Journal of Cancer, vol. 68, pp. 314-318, 1993), growthhormones, IGF-1, and antibodies to the cachexia-inducing factor TNF-α,LIF, IL-6 or oncostatin M, can also be used in combination with thepreparation of the invention.

The combination drug is preferably an insulin preparation, an insulinsensitizer, an α-glucosidase inhibitor, a biguanide, an insulinsecretagogue (preferably a sulfonylurea) or the like.

Two or more of the above-mentioned combination drugs can be used incombination in an appropriate ratio. Preferable combinations in the caseof using two or more combination drugs are, for example, as shown in thefollowing.

1) an insulin secretagogue (preferably a sulfonylurea) and anα-glucosidase inhibitor;

2) an insulin secretagogue (preferably a sulfonylurea) and a biguanide;

3) an insulin secretagogue (preferably a sulfonylurea), a biguanide andan α-glucosidase inhibitor;

4) an insulin sensitizer and an α-glucosidase inhibitor;

5) an insulin sensitizer and a biguanide;

6) an insulin sensitizer, a biguanide and an α-glucosidase inhibitor.

When the compound of the present invention or the pharmaceutical agentof the present invention is used in combination with a combination drug,the amount thereof can be reduced within a safe range in considerationof counteraction of these agents. Particularly, the dose of an insulinsensitizer, an insulin secretagogue (preferably a sulfonylurea) and abiguanide can be reduced as compared with the normal dose. Therefore, anadverse effect which may be caused by these agents can be preventedsafely. In addition, the dose of the therapeutic agent of diabeticcomplications, antihyperlipemic agent and hypotensive agent can bereduced whereby an adverse effect which may be caused by these agentscan be prevented effectively.

(12) Production Method

Hereinafter the production methods of the compound of the presentinvention are explained. Since the compounds (Ia) and (II) areencompassed in compound (I), the production method of compound (I) isexplained.

The compound (I) can be produced according to a method known per se,such as Method A to Method I shown in the following, or an analogousmethod thereto.

The compound (I-2) wherein, in the formula (I), Y is a carboxyl groupcan be produced by the following Method A.[Method A]

wherein R^(3a) is an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an optionally substitutedacyl group, and other symbols are as defined above.

As the “optionally substituted hydrocarbon group”, “optionallysubstituted heterocyclic group” and “optionally substituted acyl group”represented by R^(3a), those exemplified for R³ can be used.

According to this method, compound (I-1) is subjected to hydrolysisreaction to give compound (I-2).

The hydrolysis reaction is carried out according to a conventionalmethod in the presence of an acid or a base in a water-containingsolvent.

As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid,hydrobromic acid and the like can be used.

As the base, for example, alkaline metal carbonates such as potassiumcarbonate, sodium carbonate, cesium carbonate and the like; alkalineearth metal carbonates such as barium carbonate, calcium carbonate andthe like; alkali metal alkoxides such as sodium methoxide and the like;alkaline metal hydroxides such as potassium hydroxide, sodium hydroxide,lithium hydroxide and the like; alkaline earth metal hydroxides such asbarium hydroxide, calcium hydroxide and the like; and the like can beused.

The amount of the acid or base to be used is generally an excess amountrelative to compound (I-1). Preferably, the amount of the acid to beused is about 2about 50 equivalents relative to compound (I-1) and theamount of the base to be used is about 1.2about 5 equivalents relativeto compound (I-1).

Examples of the water-containing solvent include a mixed solvent of onekind of solvent selected from alcohols such as methanol, ethanol and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; dimethyl sulfoxide and acetone and the like, with water, and thelike. When the reaction is carried out under acidic conditions, anexcess acid may be used as a solvent.

The reaction temperature is generally from about −20° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.1 to about 20 hours.

The compound (I-2) thus obtained can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

The compound (I-1) used as a starting material compound in theabove-mentioned Method A can be produced according to the methoddescribed in, for example, Journal of Heterocyclic Chemistry, vol. 28,p. 453 (1991); Journal of Organic Chemistry, vol. 49, p. 4419 (1984);Tetrahedron Letters, vol. 34, p. 485 (1993) and the like, or a methodanalogous thereto.

The compound (I-3) having amidated carboxyl group for Y in the formula(I) is produced by, for example, the following Method B.[Method B]

wherein the symbols in the formula are as defined above.

In this method, compound (I-2) is subjected to amidation reaction togive compound (I-3). This reaction is carried out by a method known perse, such as a method comprising direct condensation of compound (I-2)and compound (VI) using a condensing agent, a method comprisingappropriate reaction of a reactive derivative of compound (I-2) withcompound (VI) and the like. Examples of the condensing agent includecondensing agents generally known, such as carbodiimide condensingagents (e.g., dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-dimethylaminopropylcarbodiimide, a hydrochloride thereof andthe like); phosphoric acid condensing agents (e.g., diethylcyanophosphate, diphenylphosphoryl azide and the like);carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborateand the like.

The solvent to be used for the reaction using a condensing agentincludes amides such as N,N-dimethylformamide, N,N-dimethylacetamide andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene and thelike; ethers such as tetrahydrofuran, dioxane, diethyl ether and thelike; ethyl acetate, water and the like. These solvents may be usedafter mixing at a suitable ratio.

The amount of Compound (VI) to be used is 0.1-10 mol equivalents,preferably 0.3-3 mol equivalents, relative to compound (I-2).

The amount of the condensing agent to be used is 0.1-10 molarequivalents, preferably 0.3-3 molar equivalents, relative to compound(I-2).

When a carbodiimide condensing agent such as dicyclohexylcarbodiimide,diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide andhydrochloride thereof and the like is used as a condensing agent, thereaction efficiency can be increased by using a suitable condensationpromoter (e.g., 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole,N-hydroxysuccinimide, N-hydroxyphthalimide and the like) as necessary.When a phosphoric acid condensing agent such as diethyl cyanophosphate,diphenylphosphoryl azide and the like is used as a condensing agent, thereaction efficiency can be generally increased by adding an organicamine base such as triethylamine and the like.

The amount of the above-mentioned condensation promoter and organicamine base to be used is 0.1-10 molar equivalents, preferably 0.3-3molar equivalents, relative to compound (I-2).

The reaction temperature is generally from about −30° C. to about 100°C.

The reaction time is generally from 0.5 to 60 hours.

In the method using a reactive derivative of compound (I-2), thereactive derivative of compound (I-2) is exemplified by acid anhydride,acid halide (acid chloride, acid bromide), imidazolide, or a mixed acidanhydride (e.g., anhydride with methyl carbonate, ethyl carbonate,isobutyl carbonate and the like) and the like.

When an acid anhydride or acid halide is used, for example, the reactionis generally carried out in the presence of a base in a solvent inert tothe reaction.

As the base, for example, triethylamine, pyridine, N-methylmorpholine,N,N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodiumhydroxide, potassium hydroxide, sodium hydrogencarbonate, sodiumcarbonate, potassium carbonate, cesium carbonate and the like can beused.

The solvent inert to the reaction is exemplified by amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; aromatichydrocarbons such as benzene, toluene and the like; ethers such astetrahydrofuran, dioxane, diethyl ether and the like; ethyl acetate,water and the like. These solvents may be used after mixing at asuitable ratio. When the above-mentioned amides are used as a solventinert to the reaction, the reaction may be carried out in the absence ofa base.

The amount of Compound (VI) to be used is 0.1-10 molar equivalents,preferably 0.3-3 molar equivalents, relative to compound (I-2). Theamount of the base to be used is 0.1-10 molar equivalents, preferably0.3-3 molar equivalents, relative to compound (I-2).

The reaction temperature is generally from about −30° C. to about 100°C.

The reaction time is generally from 0.5 to 20 hours.

When a mixed acid anhydride is used, compound (I-2) and chlorocarbonateester (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutylchlorocarbonate and the like) are reacted in the presence of a base(e.g., triethylamine, aniline, N-methylmorpholine, N,N-dimethylaniline,4-dimethylaminopyridine, sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, cesium carbonate etc.) and then reacted with compound (VI).

The amount of Compound (VI) to be used is 0.1-10 molar equivalents,preferably 0.3-3 molar equivalents, relative to compound (I-2).

The reaction temperature is generally from −30° C. to 100° C.

The reaction time is generally from 0.5 to 20 hours.

The compound (I-3) thus obtained can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

The compound (I-2) used as a starting material compound in theabove-mentioned Method B can be produced by, for example, theabove-mentioned Method A.

The compound (VI) used as a starting material compound in theabove-mentioned Method B can be produced by a method known per se.

The compound (I-4) having a hydroxy group for Y in the formula (I) canbe produced by, for example, the following Method C.[Method C]

wherein Wb is a bond or a divalent aliphatic hydrocarbon group, andother symbols are as defined above.

The “divalent aliphatic hydrocarbon group” represented by Wb isexemplified by those recited as the aforementioned W.

In this method, compound (I-1) is subjected to a reduction reaction togive compound (I-4).

This reaction is carried out according to a method known per se in thepresence of a reducing agent in a solvent inert to the reaction.

Examples of the reducing agent include sodium borohydride, lithiumborohydride, lithium aluminum hydride, diisobutylaluminum hydride,sodium dihydrobis(2-methoxyethoxy)aluminate, borane and a complexthereof (e.g., borane-tetrahydrofuran, pyridineborane,borane-dimethylsulfide and the like) and the like.

The amount of the reducing agent to be used is preferably about 0.5about10 molar equivalents relative to compound (I-1).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; ethers such as tetrahydrofuran, dioxane,diethyl ether and the like; water, alcohols such as methanol, ethanol,isopropanol and the like; and the like. These solvents may be used aftermixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (I-4) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

The compound (I-5) having a group represented by the formula: —OCOR⁴ (R⁴is as defined above) for Y in the formula (I) is produced by, forexample, the following Method D.[Method D]

wherein the symbols in the formula are as defined above.

In this method, compound (I-4) is subjected to acylation reaction togive compound (I-5). This reaction can be carried out by a method knownper se. Such method is exemplified by a method comprising directcondensation of compound (I-4) with carboxylic acid derivative (R⁴CO₂H)using a condensing agent, a method comprising appropriate reaction of areactive derivative of carboxylic acid derivative (R⁴CO₂H) with compound(I-4) and the like. Here, the method comprising direct condensation ofcompound (I-4) with carboxylic acid derivative (R⁴CO₂H) using acondensing agent is performed in the same manner as in theaforementioned “direct condensation of compound (I-2) with compound (VI)using a condensing agent”.

In the method using a reactive derivative of the carboxylic acidderivative, the reactive derivative of the carboxylic acid derivativeis, for example, acid anhydride, acid halide (acid chloride, acidbromide), imidazolide, a mixed acid anhydride (e.g., anhydride withmethyl carbonate, ethyl carbonate, isobutyl carbonate and the like), andthe like.

For example, when an acid anhydride or an acid halide is used, thereaction is generally carried out in a solvent inert to the reaction inthe presence of a base.

The base is, for example, triethylamine, pyridine, N-methylmorpholine,N,N-dimethylaniline, 4-dimethylaminopyridine, lithium hydroxide, sodiumhydroxide, potassium hydroxide, sodium hydrogencarbonate, sodiumcarbonate, potassium carbonate, cesium carbonate and the like.

The solvent inert to the reaction is exemplified by amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; aromatichydrocarbons such as benzene, toluene and the like; ethers such astetrahydrofuran, dioxane, diethyl ether and the like; ethyl acetate,water and the like. These solvents may be used after mixing at asuitable ratio. When the above-mentioned amides are used as the solventinert to the reaction, the reaction may be carried out in the absence ofa base.

The amount of the reactive derivative of carboxylic acid to be used is0.1-10 molar equivalents, preferably 0.3-3 molar equivalents, relativeto compound (I-4). The amount of the base to be used is 0.1-10 molarequivalents, preferably 0.3-3 molar equivalents, relative to compound(I-4).

The reaction temperature is generally from −30° C. to 100° C.

The reaction time is generally from 0.5 to 20 hours.

When a mixed acid anhydride is used, a carboxylic acid derivative(R⁴CO₂H) and a chlorocarbonate ester (e.g., methyl chlorocarbonate,ethyl chlorocarbonate, isobutyl chlorocarbonate and the like) arereacted in the presence of a base (e.g., triethylamine, aniline,N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine,lithium hydroxide, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, sodium carbonate, potassium carbonate, cesiumcarbonate and the like), and then reacted with compound (I-4).

The amount of the carboxylic acid derivative to be used is 0.1-10 molarequivalents, preferably 0.3-3 molar equivalents, relative to compound(I-4).

The reaction temperature is generally from −30° C. to 100° C.

The reaction time is generally from 0.5 to 20 hours.

The thus-obtained compound (I-5) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

The compound (I-4) used as a starting material compound in theabove-mentioned Method D is produced by, for example, theabove-mentioned Method C.

The compound (I-6) having a group represented by the formula: —OR^(3a)(R^(3a) is as defined above) for Y in the formula (I) can be producedby, for example, the following Method E and Method F.[Method E]

wherein X is a hydroxy group, a halogen atom or a group represented bythe formula: —OSO₂R⁸ (R⁸ is alkyl having 1 to 4 carbon atoms or arylgroup having 6 to 10 carbon atoms optionally substituted by alkyl having1 to 4 carbon atoms), and other symbols are as defined above.

As used herein, the alkyl having 1 to 4 carbon atoms of the “alkylhaving 1 to 4 carbon atoms” and the “aryl group having 6 to 10 carbonatoms optionally substituted by alkyl having 1 to 4 carbon atoms”represented by R⁸ is exemplified by methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl and the like, with preference givento methyl.

The aryl group having 6 to 10 carbon atoms of the “aryl group having 6to 10 carbon atoms optionally substituted alkyl having 1 to 4 carbonatoms” represented by R⁸ is exemplified by phenyl, naphthyl and thelike, with preference given to phenyl.

In this method, compound (I-6) is produced by the reaction of compound(I-4) with compound (VII).

When X is a hydroxy group, this reaction is carried out by a methodknown per se, such as a method described in, for example, Synthesis p. 1(1981), or a method analogous thereto. That is, this reaction isgenerally carried out in the presence of an organic phosphorus compoundand electrophile in a solvent that does not adversely influence thereaction.

The organic phosphorus compound is, for example, triphenylphosphine,tributylphosphine and the like.

The electrophile is, for example, diethyl azodicarboxylate, diisopropylazodicarboxylate, azodicarbonyldipiperidine and the like.

The amount of the organic phosphorus compound and electrophile to beused is preferably about 1about 5 molar equivalent, relative to compound(I-4).

The solvent that does not adversely influence the reaction isexemplified by ethers such as diethyl ether, tetrahydrofuran, dioxaneand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; amides such as N,N-dimethylformamide andthe like; sulfoxides such as dimethyl sulfoxide and the like; and thelike. These solvents may be used after mixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

When X is a halogen atom or a group represented by the formula: —OSO₂R⁸(R⁸ is as defined above), this reaction is carried out according to aconventional method in the presence of a base in a solvent that does notadversely influence the reaction.

The base is exemplified by alkali metal salts such as lithium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate,potassium carbonate, cesium carbonate and the like; alkaline earth metalsalts such as barium carbonate, calcium carbonate, barium hydroxide,calcium hydroxide and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t-butoxide and the like; and the like.

The amount of these bases to be used is preferably about 1-about 5 molarequivalents relative to compound (I-4).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. These solvents may be used aftermixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (I-6) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.[Method F]

wherein E is a halogen atom or a group represented by the formula:—OSO₂R⁸ (R⁸ is as defined above), and other symbols are as definedabove.

In this method, compound (I-6) is produced by reacting compound (III-1)with compound (VIII).

This reaction is carried out according to a conventional method in thepresence of a base in a solvent that does not adversely influence thereaction.

The base is exemplified by alkali metal salts such as lithium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, sodiumcarbonate, potassium carbonate, cesium carbonate and the like; alkalineearth metal salts such as barium carbonate, calcium carbonate, bariumhydroxide, calcium hydroxide and the like; amines such as pyridine,triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-eneand the like; metal hydrides such as potassium hydride, sodium hydrideand the like; alkali metal alkoxides such as sodium methoxide, sodiumethoxide, potassium t-butoxide and the like; and the like.

The amount of the base to be used is preferably about 1-about 5 molarequivalents relative to compound (III-1).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; and the like. These solvents may be used aftermixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (I-6) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

A compound having an esterified carboxyl group for Y, and —CH═CH— or—(CH₂)₂— for W in the formula (I) [compound (I-9) or (1-10),respectively] is produced by the following Method G.[Method G]

wherein the symbols in the formula are as defined above.(Step 1) Reduction Reaction

This reaction is carried our according to a conventional method in thepresence of a reducing agent in a solvent inert to the reaction.

The reducing agent is, for example, sodium borohydride, lithiumborohydride, lithium aluminum hydride, diisobutylaluminum hydride,sodium dihydrobis(2-methoxyethoxy)aluminate, borane and a complexthereof (e.g., borane-tetrahydrofuran, pyridineborane,borane-dimethylsulfide and the like), and the like.

The amount of the reducing agent to be used is preferably about0.5-about 10 molar equivalents relative to compound (I-7).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; ethers such as tetrahydrofuran, dioxane,diethyl ether and the like; water, alcohols such as methanol, ethanol,isopropanol and the like; and the like. These solvents may be used aftermixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (I-8) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

The compound (I-7) used as a starting material compound in step 1 of theabove-mentioned Method G can be produced by the method described in, forexample, Journal of Heterocyclic Chemistry, vol. 28, p. 453 (1991);Journal of Organic Chemistry, vol. 49, p. 4419 (1984); TetrahedronLetters, vol. 34, p. 485 (1993) and the like or a method analogousthereto.

(Step 2) Oxidization Reaction

This reaction is carried out according to a conventional method in thepresence of an oxidant in a solvent inert to the reaction.

The oxidant is, for example, a metal oxidant such as manganese dioxide,pyridinium chlorochromate, pyridinium dichromate, ruthenium oxide andthe like, and the like.

The amount of the oxidant to be used is preferably about 1-about 10molar equivalents relative to compound (I-8).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; and the like. These solvents may be used after mixing at asuitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The compound (IV) can be also produced by adding a reaction reagent suchas a sulfur trioxide-pyridine complex or oxalyl chloride and the like tocompound (I-8) in a mixed solvent of sulfoxides such as dimethylsulfoxide and the like with halogenated hydrocarbons such as chloroform,dichloromethane and the like, and reacting the compound with an organicbase such as triethylamine, N-methylmorpholine and the like.

The amount of the reaction reagent to be used is preferably about1-about 10 molar equivalents relative to compound (I-8).

The amount of the organic base to be used is preferably about 1-about 10molar equivalents relative to compound (I-8).

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (IV) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

(Step 3) Carbon-Addition Reaction

In this reaction, compound (I-9) is produced by the reaction of anorganic phosphorus reagent with compound (IV) in the presence of a base.

This method is conducted according to a conventional method in thepresence of a base in a solvent inert to the reaction.

The organic phosphorus reagent is, for example, methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate, ethyldimethylphosphonoacetate and the like.

The amount of the organic phosphorus reagent to be used is preferablyabout 1-about 10 molar equivalents relative to compound (IV).

The base is exemplified by alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogencarbonate, potassiumcarbonate and the like; alkaline earth metal salts such as bariumcarbonate, calcium carbonate, barium hydroxide, calcium hydroxide andthe like; amines such as pyridine, triethylamine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undeca-7-ene and the like; metal hydrides such aspotassium hydride, sodium hydride and the like; alkali metal alkoxidessuch as sodium methoxide, sodium ethoxide, potassium t-butoxide and thelike; and the like.

The amount of the base to be used is preferably about 1-about 5 molarequivalents relative to compound (IV).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; amides such as N,N-dimethylformamide and the like;sulfoxides such as dimethyl sulfoxide and the like; and the like. Thesesolvents may be used after mixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (I-9) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

(Step 4) Hydrogenation Reaction

This method is conducted according to a conventional method in a solventinert to the reaction under a hydrogen atmosphere or in the presence ofa hydrogen source such as formic acid and the like and a metal catalyst.

The metal catalyst is exemplified by transition metal catalysts such aspalladium-carbon, palladium-barium carbonate, palladium black, platinumoxide, platinum-carbon, Raney nickel, Wilkinson catalyst and the like,and the like.

The amount of these transition metal catalysts to be used is preferablyabout 0.01-about 10 molar equivalents relative to compound (I-9).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; amides such as N,N-dimethylformamide and the like;alcohols such as methanol, ethanol, isopropanol and the like; and thelike. These solvents may be used after mixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (I-10) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, solvent substitution, chromatographyand the like.

The compound (I-11) having a carboxyl group for Y and —(CH₂)₂— for W inthe formula (I) can be also produced by the following Method H.[Method H]

wherein the symbols in the formula are as defined above.(Step 1) Carbon-Addition Reaction

In this method, compound (V) is produced by subjecting compound (III-2)to 2 carbons-addition reaction using malonic acid diester.

This reaction is conducted according to a conventional method in thepresence of malonic acid diester and a base in a solvent that does notadversely influence the reaction.

The base is exemplified by alkali metal salts such as lithium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate,potassium carbonate, cesium carbonate and the like; alkaline earth metalsalts such as barium carbonate, calcium carbonate, barium hydroxide,calcium hydroxide and the like; amine such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium t-butoxide and the like; and the like.

The malonic acid diester is, for example, diethyl malonate, dimethylmalonate, dipropyl malonate, dibutyl malonate and the like.

The amount of the base and malonic acid diester to be used is preferablyabout 1-about 5 molar equivalents relative to compound (III-2).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; and the like. These solvents may beused after mixing at a suitable ratio.

The reaction temperature is generally from about −50° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.5 to about 20 hours.

The thus-obtained compound (V) can be isolated and purified by a knownseparation and purification means, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, solvent substitution, chromatography and the like.

(Step 2) Decarbonation Reaction

In this method, compound (I-11) is produced by subjecting compound (V)to a decarbonation reaction.

This decarbonation reaction is carried out according to a conventionalmethod under acidic conditions or basic conditions.

When the reaction is carried out under acidic conditions, this method isconducted according to a conventional method in a solvent inert to thereaction.

The acid is, for example, hydrochloric acid, sulfuric acid, acetic acid,hydrobromic acid and the like.

The amount of the acid to be used is generally an excess amount ofcompound (V), preferably about 2-about 50 equivalents, relative tocompound (V).

The solvent inert to the reaction is, for example, a mixed solvent ofwater and one or more kinds selected from alcohols such as methanol,ethanol and the like; ketones such as acetone, 2-butanone and the like;and the like. Alternatively, an excess acid may be used as a solvent.

When the reaction is carried out under basic conditions, this method isconducted according to a conventional method comprising hydrolysis toconvert compound (V) to dicarboxylic acid, and then pyrolysis to givecompound (I-11).

The hydrolysis reaction is carried out according to a conventionalmethod in the presence of a base in a water-containing solvent that doesnot influence the reaction.

The base is exemplified by alkali metal salts such as lithium hydroxide,sodium hydroxide, potassium hydroxide, potassium carbonate, sodiumcarbonate, cesium carbonate and the like; alkaline earth metal saltssuch as barium carbonate, calcium carbonate, barium hydroxide, calciumhydroxide and the like; alkali metal alkoxides such as sodium methoxideand the like; and the like.

The amount of the base to be used is generally an excess amount ofcompound (V), preferably about 2.5-about 20 equivalent, relative tocompound (V).

The water-containing solvent that does not influence the reaction is,for example, a mixed solvent of one or more kinds selected from alcoholssuch as methanol, ethanol and the like; ethers such as tetrahydrofuran,dioxane, diethyl ether and the like; dimethyl sulfoxide and acetone andthe like, with water; and the like.

The reaction temperature is generally from about −20° C. to about 150°C., preferably from about −10° C. to about 100° C.

The reaction time is generally from about 0.1 to about 20 hours.

This pyrolysis reaction is carried out according to a conventionalmethod in a solvent inert to the reaction.

The solvent inert to the reaction is, for example, pyridine, quinoline,collidine and the like.

The reaction temperature is generally from about −20° C. to about 250°C., preferably from about 50° C. to about 200° C.

The reaction time is generally from about 0.1 to about 20 hours.

The thus-obtained compound (I-11) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, solvent substitution, chromatographyand the like.

Of the compounds (III-1) used as a starting material compound in MethodF, a compound wherein E is a halogen atom or a group represented by theformula: —OSO₂R⁸ (R⁸ is as defined above) can be produced by, forexample, the following Method I. The compound (III-1) encompassescompound (III-2) used as a starting material compound in Method H.

wherein each symbol is as defined above.

The compound (III-1) wherein E is a halogen atom can be produced by, forexample, reacting compound (I-4) with a halogenating agent.

This method is conducted according to a conventional method in thepresence of a halogenating agent in a solvent inert to the reaction.

The halogenating agent is, for example, thionyl chloride or phosphorustribromide and the like.

The amount of the halogenating agent to be used is preferably about1-about 20 molar equivalents relative to compound (I-4).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like and the like. These solvents may be used after mixing at asuitable ratio. Alternatively, an excess halogenating agent may be usedas a solvent.

The reaction temperature is generally from about −20° C. to about 150°C., preferably from about 0° C. to about 100° C.

The reaction time is generally from about 0.1 to about 20 hours.

The compound (III-1) wherein E is a group represented by the formula:—OSO₂R⁸ (R⁸ is as defined above) is produced by, for example, reactingcompound (I-4) with a sulfonylating agent in the presence of a suitablebase.

This method is conducted according to a conventional method in thepresence of a sulfonylating agent in a solvent inert to the reaction.

The sulfonylating agent is, for example, mesyl chloride, tosyl chlorideor benzenesulfonyl chloride and the like. In this case, compound (I-1)wherein E is mesyloxy, tosyloxy and benzenesulfonyloxy respectively, isproduced.

The amount of the sulfonylating agent and base to be used is preferablyabout 1-about 2 molar equivalents relative to compound (I-4).

The solvent that does not adversely influence the reaction isexemplified by aromatic hydrocarbons such as benzene, toluene, xyleneand the like; ethers such as tetrahydrofuran, dioxane, diethyl ether andthe like; amides such as N,N-dimethylformamide, N,N-dimethylacetamideand the like; halogenated hydrocarbons such as chloroform,dichloromethane and the like; ethyl acetate, acetone and the like. Thesesolvents may be used after mixing at a suitable ratio.

The reaction temperature is generally from about −20° C. to about 150°C., preferably from about 0° C. to about 100° C.

The reaction time is generally from about 0.1 to about 20 hours.

The thus-obtained compound (III-1) can be isolated and purified by aknown separation and purification means, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, solvent substitution, chromatographyand the like.

In each of the aforementioned reactions, when the starting materialcompound has amino, carboxy, hydroxy or carbonyl as a substituent, thesegroups may have a protecting group introduced therein, such as onegenerally used in peptide chemistry and the like. The objective compoundcan be obtained by removing the protecting group as necessary after thereaction.

The amino-protecting group is, for example, formyl, C₁₋₆ alkyl-carbonyl(e.g., acetyl, propionyl and the like), C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like),benzoyl, C₇₋₁₃ aralkyl-carbonyl (e.g., benzylcarbonyl and the like),C₇₋₁₃ aralkyloxy-carbonyl (e.g., benzyloxycarbonyl,9-fluorenylmethoxycarbonyl and the like), trityl, phthaloyl,N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl, triethylsilyl,dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl andthe like), C₂₋₆ alkenyl (e.g., 1-allyl and the like) and the like. Thesegroups are optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like), C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy and the like) or nitro and the like.

The carboxy-protecting group is, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, tert-butyl and the like), C₇₋₁₃ aralkyl(e.g., benzyl and the like), phenyl, trityl, silyl (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like), C₂₋₆alkenyl (e.g., 1-allyl and the like) and the like. These groups areoptionally substituted by 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine and the like), C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy and the like) or nitro and the like.

The hydroxy-protecting group is, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl,trityl, C₇₋₁₃ aralkyl (e.g., benzyl and the like), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl and the like), benzoyl, C₇₋₁₃aralkyl-carbonyl (e.g., benzylcarbonyl and the like),2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl and the like), C₂₋₆ alkenyl (e.g., 1-allyl andthe like) and the like. These groups are optionally substituted by 1 to3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike), C₁₋₆ alkyl (e.g., methyl, ethyl, propyl and the like), C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy and the like) or nitro and thelike.

The carbonyl-protecting group is, for example, cyclic acetal (e.g.,1,3-dioxane and the like), non-cyclic acetal (e.g., di-C₁₋₆ alkyl acetaland the like) and the like.

These protecting groups can be eliminated according to a method knownper se, such as a method described in Protective Groups in OrganicSynthesis, John Wiley and Sons (1980) and the like. For example,employed is a method using acid, base, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,trimethylsilyl bromide and the like) and the like, reduction and thelike.

When the starting material compound can form a salt in each of theaforementioned reactions, the compound in the form of a salt may beused. The salt is, for example, the salt of compound (I) exemplifiedabove.

When compound (I) contains an optical isomer, a stereoisomer, apositional isomer or a rotational isomer, these are also encompassed incompound (I), and can be obtained as a single product according to asynthetic method and separation method known per se. For example, whencompound (I) has an optical isomer, an optical isomer resolved from thiscompound is also encompassed in compound (I).

The optical isomer can be produced by a method known per se. To bespecific, an optically active synthetic intermediate is used, or thefinal racemate product is subjected to optical resolution according to aconventional method to give an optical isomer.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method and the like.

1) Fractional Recrystallization Method

A salt of a racemate with an optically active compound (e.g.,(+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaricacid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine,(−)-cinchonidine, brucine and the like) is formed, which is separated bya fractional recrystallization method, and applied, where desired, to aneutralization step to give a free optical isomer.

2) Chiral Column Method

A racemate or a salt thereof is applied to a column for separation of anoptical isomer (chiral column) to allow separation. In the case of aliquid chromatography, for example, a mixture of an optical isomer isapplied to a chiral column such as ENANTIO-OVM (manufactured by TosohCorporation) or CHIRAL series (manufactured by Daicel ChemicalIndustries, Ltd.) and the like, and eluted with water, various buffers(e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol,isopropanol, acetonitrile, trifluoroacetic acid, diethylamine and thelike) solely or in admixture to separate the optical isomer. In the caseof a gas chromatography, for example, a chiral column such asCP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like isused to allow separation.

3) Diastereomer Method

A racemic mixture is prepared into a diastereomeric mixture by chemicalreaction with an optically active reagent, which is separated into asingle material by a typical separation means (e.g., fractionalrecrystallization, chromatography method and the like) and the like, andsubjected to a chemical treatment such as hydrolysis and the like toseparate an optically active reagent moiety, whereby an optical isomeris obtained. For example, when compound (I) contains hydroxy or primaryor secondary amino in a molecule, the compound and an optically activeorganic acid (e.g., MTPA [α-methoxy-α-(trifluoromethyl)phenylaceticacid], (−)-menthoxyacetic acid and the like) and the like are subjectedto condensation to give an ester form or amide form diastereomer. Whencompound (I) has a carboxylic acid group, this compound and an opticallyactive amine reagent or an optically active alcohol reagent aresubjected to condensation to give an amide form or ester formdiastereomer. The separated diastereomer is converted to an opticalisomer of the original compound by acid hydrolysis or base hydrolysis.

The present invention further relates to a glucose-dependent insulinsecretagogue containing an isoxazole derivative.

As used herein, the isoxazole derivative is not particularly limited aslong as it has an isoxazole skeleton. Examples of the isoxazolederivative include a compound having a group represented by the formula:—W—Y (W and Y are as defined above) at the 4-position of the isoxazoleskeleton, and the like.

The isoxazole derivative is preferably compound (I) or a salt thereof ora prodrug thereof, more preferably compound (II) or a salt thereof or aprodrug thereof.

The glucose-dependent insulin secretagogue means a pharmaceutical agentthat shows a selective insulin secretion promoting action in thepresence of high concentration glucose (e.g., patients showing fastingblood glucose level of not less than 126 mg/dl or 75 g oral glucosetolerance test (75 g OGTT) 2 h level of not less than 140 mg/dl and thelike). Therefore, the glucose-dependent insulin secretagogue of thepresent invention is useful as a safe agent for the prophylaxis ortreatment of diabetes, which is associated with a low risk of vascularcomplications, induction of hypoglycemia and the like, which are thenegative effects caused by insulin.

The glucose-dependent insulin secretagogue of the present invention canbe produced in the same manner as in the aforementioned pharmaceuticalcomposition and can be used safely for a mammal (e.g., human, mouse,rat, rabbit, dog, cat, bovine, horse, swine, monkey etc.).

The dose and the administration method of the glucose-dependent insulinsecretagogue of the present invention are the same as those for theaforementioned compounds of the present invention. Moreover, theglucose-dependent insulin secretagogue of the present invention can bealso used in combination with the aforementioned combination drug.

The present invention is explained in detail in the following byreferring to Experimental Examples, Reference Examples, Examples andPreparation Examples, which are not to be construed as limitative.

In the following Reference Examples and Examples, “% means percent byweight unless specifically indicated. In addition, room temperaturemeans a temperature of 1-30° C.

In Examples, HPLC was measured under the following conditions.

measurement tool: LC-10Avp system, Shimadzu Seisakusho

column: CAPSEL PAK C18UG120 S-3 μm, 2.0×50 mm solvent:

-   -   Solution A; 0.1% trifluoroacetic acid-containing water,    -   Solution B; 0.1% trifluoroacetic acid-containing acetonitrile        gradient cycle: 0.00 min (Solution A/Solution B=90/10), 4.00 min        (Solution A/Solution B=5/95), 5.50 min (Solution A/Solution        B=5/95), 5.51 min (Solution A/Solution B=90/10), 8.00 min        (Solution A/Solution B=90/10)        injection amount: 2 μl, flow rate: 0.5 ml/min, detection method:        UV 220 nm

In Examples, mass spectrum (MS) was measured under the followingconditions.

measurement tool: Micromass Ltd., platform II, Waters Corporation ZQ, orWaters Corporation ZMD

ionization method: Atmospheric Pressure Chemical Ionization: APCI orElectron Spray Ionization: ESI

preparative HPLC apparatus: Gilson, Inc., high through-put purificationsystem

column: YMC Combiprep ODS-A S-5 μm, 50×20 mm

solvent:

-   -   Solution A; 0.1% trifluoroacetic acid-containing water,    -   Solution B; 0.1% trifluoroacetic acid-containing acetonitrile        gradient cycle: 0.00 min (Solution A/Solution B=90/10), 1.20 min        (Solution A/Solution B=90/10), 4.75 min (Solution A/Solution        B=0/100), 7.30 min (Solution A/Solution B=0/100), 7.40 min        (Solution A/Solution B=90/10), 7.50 min (Solution A/Solution        B=90/10)        flow rate: 25 ml/min, detection method: UV 220 nm

EXAMPLES Experimental Example 1

Hypoglycemic Action in Rats

Male SD rats (7 weeks of age, 5 per group) were fasted overnight andblood was drawn from the tail vein to measure the glucose level beforeadministration of the test compound. Then the test compound (30 mg/kgbody weight/10 mL (compounds of Examples 8, 16, 66, 68, 79, 94, 123) or50 mg/kg body weight/10 mL (compounds of Examples 58, 70)) suspended in0.5% methyl cellulose was orally administered to the rats using agastric tube. Oral glucose tolerance test (2 g/kg body weight/10 mL) wasstarted 60 min later. Blood was drawn at 30 min after starting theglucose loading, and glucose level was measured. The glucose level wasmeasured using an automatic analyzer (HITACHI 7070). The glucose levelof the test compound group is expressed in a value (%) relative to thecontrol group and shown in Table 1. TABLE 1 test compound glucose level(Example No.) (% of control) 8 85 16 88 58 85 66 80 68 75 70 88 79 77 9481 123 86

As shown above, the compound of the present invention has a superiorblood glucose level-lowering effect, and is useful as an agent for theprophylaxis or treatment of diabetes and the like.

Experimental Example 2

Insulin Secretion Promoting Action in Pancreatic Langerhans' Islet ofRats

The pancreas of 8-week-old male SD rat was treated with collagenase andthe isolated Langerhans' islet was preincubated for 1 hr in a medium(KRB) containing 2.8 mmol/L glucose in a 24 well incubation plate, whichwas followed by incubation for 1 hr in KRB containing the test compound(100 mol/L, see Table 2) and 7.5 mmol/L glucose (control group was freeof test compound). The medium was recovered and the amount of thesecreted insulin was measured using a radioimmunoassay kit (trademark:SHIONORIA insulin kit (manufactured by Shionogi & Co., Ltd.)). TheLangerhans' islet was lysed by ultrasonication and the DNA amount wasmeasured, based on which the insulin level in the medium was amended.The insulin secretion amount of the test compound group is expressed ina value (%) relative to the control group and shown in Table 2. TABLE 2Test compound insulin secretion (Example No.) promoting action (%) 8 25664 273 70 235 77 201 92 156

As shown above, the compound of the present invention has a superiorinsulin secretion promoting action, and is useful as an agent for theprophylaxis or treatment of diabetes and the like.

Reference Example 1

A mixture of 4′-trifluoromethoxyacetophenone (6.30 g), sodium hydride(60%, oil, 1.22 g) and diethyl carbonate (70 ml) was stirred at 80° C.for 1 hr. Water was added to the reaction mixture, and the aqueous layerwas neutralized with dilute hydrochloric acid. Then, the mixture wasstirred at room temperature for 30 min, and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. A mixture of the residue andN,N-dimethylformamide dimethylacetal (5.54 g) was refluxed for 1.5 hr.The reaction mixture was concentrated, and the residue was dissolved inethanol (120 ml). To the obtained solution was added hydroxylaminehydrochloride (4.29 g) and the mixture was refluxed for 5 hr. Thereaction mixture was concentrated, dilute hydrochloric acid was added tothe residue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and ethyl5-(4-trifluoromethoxyphenyl)isoxazole-4-carboxylate (6.60 g, yield 71%)was obtained as a yellow oil from a fraction eluted with ethylacetate-hexane (1:2, volume ratio). NMR (CDCl₃) δ: 1.38 (3H, t, J=7.0Hz), 4.36 (2H, q, J=7.0 Hz), 7.35 (2H, d, J=8.8 Hz), 8.22 (2H, d, J=8.8Hz), 8.64 (1H, s).

Reference Example 2

To a solution of ethyl5-(4-trifluoromethoxyphenyl)isoxazole-4-carboxylate (6.60 g) intetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.0M tetrahydrofuran solution, 55 ml) at 0° C. The mixture was stirred atroom temperature for 30 min. The reaction mixture was poured into dilutehydrochloric acid and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated to give 5-(4-trifluoromethoxyphenyl)-4-isoxazolylmethanol(5.70 g, yield 99%) as colorless crystals. The crystals wererecrystallized from ethyl acetate-hexane. melting point: 45-46° C.

Reference Example 3

A mixture of 4′-trifluoromethylacetophenone (10.0 g), sodium hydride(60%, oil, 2.13 g) and diethyl carbonate (80 ml) was stirred at 80° C.for 90 min. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionatewas obtained as an oil from a fraction eluted with ethyl acetate-hexane(1:9, volume ratio). A mixture of this oil and N,N-dimethylformamidedimethylacetal (9.50 g) was refluxed for 1 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethanol (80 ml). To theobtained solution was added hydroxylamine hydrochloride (7.39 g), andthe mixture was refluxed for 2 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, the crystals obtainedfrom a fraction eluted with ethyl acetate-hexane (1:9, volume ratio)were recrystallized from hexane to give ethyl5-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (8.42 g, yield 56%)as a colorless prism. melting point: 53-54° C.

Reference Example 4

A mixture of N-methoxy-N-methylamine hydrochloride (9.28 g),triethylamine (14 ml) and N,N-dimethylformamide (500 ml) was stirred atroom temperature for 30 min. 5-Phenylisoxazole-4-carboxylic acid (14.95g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (14.08 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.00 g)were added and the mixture was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-methoxy-N-methyl-(5-phenyl-4-isoxazolyl)carbamide (13.95 g, yield 76%)was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:4, volume ratio). NMR (CDCl₃) δ: 3.36 (3H, s), 3.57(3H, s), 7.44-7.56 (3H, m), 7.86-7.98 (2H, m), 8.52 (1H, s).

Reference Example 5

To a solution of N-methoxy-N-methyl-(5-phenyl-4-isoxazolyl)carbamide(13.01 g) in tetrahydrofuran (200 ml) was gently addeddiisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 120 ml) at0° C. and the mixture was stirred at room temperature for 30 min. Thereaction mixture was poured into dilute hydrochloric acid and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and5-phenylisoxazole-4-carbaldehyde (8.54 g, yield 88%) was obtained as acolorless oil from a fraction eluted with ethyl acetate-hexane (1:4,volume ratio). NMR (CDCl₃) δ: 7.53-7.66 (3H, m), 7.87-7.96 (2H, m), 8.72(1H, s), 10.10 (1H, s).

Reference Example 6

A mixture of methyl 4′-fluorobenzoylacetate (10.02 g) andN,N-dimethylformamide dimethylacetal (8.63 g) was refluxed for 1.5 hr.The reaction mixture was concentrated, and the residue was dissolved inethanol (150 ml). To the obtained solution was added hydroxylaminehydrochloride (6.75 g) and the mixture was refluxed for 5 hr. Thereaction mixture was concentrated, dilute hydrochloric acid was added tothe residue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 5-(4-fluorophenyl)isoxazole-4-carboxylate(9.75 g, yield 91%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:4, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 92-93° C.

Reference Example 7

To a solution of methyl 5-(4-fluorophenyl)isoxazole-4-carboxylate (7.06g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(4-fluorophenyl)-4-isoxazolylmethanol (6.35 g, yield 90%) as colorlesscrystals. The crystals were recrystallized from ethyl acetate-hexane.melting point: 41-42° C.

Reference Example 8

A mixture of 3′,4′-difluoroacetophenone (10.27 g), sodium hydride (60%,oil, 2.60 g) and diethyl carbonate (150 ml) was stirred at 80° C. for 1hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (11.80 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (200 ml). Tothe obtained solution was added hydroxylamine hydrochloride (9.18 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3,4-difluorophenyl)isoxazole-4-carboxylate (11.60 g, yield 70%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 64-65° C.

Reference Example 9

To a solution of ethyl 5-(3,4-difluorophenyl)isoxazole-4-carboxylate(6.68 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 75 ml) at 0° C. The mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give5-(3,4-difluorophenyl)-4-isoxazolylmethanol (6.68 g, yield 92%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 72-73° C.

Reference Example 10

A mixture of 4′-bromoacetophenone (9.00 g), sodium hydride (60%, oil,1.80 g) and diethyl carbonate (100 ml) was stirred at 80° C. for 1 hr.Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.10 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (150 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.33 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(4-bromophenyl)isoxazole-4-carboxylate (10.17 g, yield 76%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 47-48° C.

Reference Example 11

To a solution of ethyl 5-(4-bromophenyl)isoxazole-4-carboxylate (9.50 g)in tetrahydrofuran (70 ml) was gently added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 70 ml) at 0° C. The mixture was stirredat room temperature for 30 min. The reaction mixture was poured intodilute hydrochloric acid and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give 5-(4-bromophenyl)-4-isoxazolylmethanol(8.03 g, yield 98%) as colorless crystals. The crystals wererecrystallized from ethyl acetate-hexane. melting point: 104-105° C.

Reference Example 12

A mixture of ethyl 4′-nitrobenzoylacetate (10.61 g) andN,N-dimethylformamide dimethylacetal (8.06 g) was refluxed for 1.5 hr.The reaction mixture was concentrated, and the residue was dissolved inethanol (200 ml). To the obtained solution was added hydroxylaminehydrochloride (6.33 g) and the mixture was refluxed for 5 hr. Thereaction mixture was concentrated, dilute hydrochloric acid was added tothe residue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and ethyl 5-(4-nitrophenyl)isoxazole-4-carboxylate (9.78g, yield 83%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:4, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 78-79° C.

Reference Example 13

To a solution of ethyl 5-(4-nitrophenyl)isoxazole-4-carboxylate (9.06 g)in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give 5-(4-nitrophenyl)-4-isoxazolylmethanol(7.16 g, yield 94%) as colorless crystals. The crystals wererecrystallized from ethyl acetate-hexane. melting point: 170-171° C.

Reference Example 14

A mixture of 3′-chloroacetophenone (7.00 g), sodium hydride (60%, oil,1.80 g) and diethyl carbonate (100 ml) was stirred at 80° C. for 1 hr.Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.15 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.30 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3-chlorophenyl)isoxazole-4-carboxylate (9.13 g, yield 80%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 77-78° C.

Reference Example 15

To a solution of ethyl 5-(3-chlorophenyl)isoxazole-4-carboxylate (8.50g) in tetrahydrofuran (80 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(3-chlorophenyl)-4-isoxazolylmethanol (6.87 g, yield 97%) as colorlesscrystals. The crystals were recrystallized from ethyl acetate-hexane.melting point: 80-81° C.

Reference Example 16

A mixture of 5-acetyl-1,3-benzodioxole (7.45 g), sodium hydride (60%,oil, 1.80 g) and diethyl carbonate (100 ml) was stirred at 80° C. for 1hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.30 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.33 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(1,3-benzodioxol-5-yl)isoxazole-4-carboxylate (9.49 g, yield 80%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 73-74° C.

Reference Example 17

To a solution of ethyl 5-(1,3-benzodioxol-5-yl)isoxazole-4-carboxylate(8.56 g) in tetrahydrofuran (70 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 70 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(1,3-benzodioxol-5-yl)-4-isoxazolylmethanol (6.97 g, yield 97%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 92-93° C.

Reference Example 18

A mixture of 3′-chloro-4′-fluoroacetophenone (9.54 g), sodium hydride(60%, oil, 2.15 g) and diethyl carbonate (100 ml) was stirred at 800 for1 hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (9.63 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (7.47 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3-chloro-4-fluorophenyl)isoxazole-4-carboxylate (10.33 g, yield 71%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 106-107° C.

Reference Example 19

To a solution of ethyl5-(3-chloro-4-fluorophenyl)isoxazole-4-carboxylate (9.50 g) intetrahydrofuran (75 ml) was gently added diisobutylaluminum hydride (1.0M tetrahydrofuran solution, 75 ml) at 0° C. and the mixture was stirredat room temperature for 30 min. The reaction mixture was poured intodilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give5-(3-chloro-4-fluorophenyl)-4-isoxazolylmethanol (7.58 g, yield 95%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 106-107° C.

Reference Example 20

A mixture of 3′,4′-dimethoxyacetophenone (9.20 g), sodium hydride (60%,oil, 1.99 g) and diethyl carbonate (100 ml) was stirred at 80° C. for 1hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.95 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.98 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3,4-dimethoxyphenyl)isoxazole-4-carboxylate (10.81 g, yield 78%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 113-114° C.

Reference Example 21

To a solution of ethyl 5-(3,4-dimethoxyphenyl)isoxazole-4-carboxylate(8.40 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 65 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(3,4-dimethoxyphenyl)-4-isoxazolylmethanol (6.85 g, yield 96%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 83-84° C.

Reference Example 22

A mixture of 4′-chloro-3′-fluoroacetophenone (12.50 g), sodium hydride(60%, oil, 2.88 g) and diethyl carbonate (150 ml) was stirred at 80° C.for 1 hr. Water was added to the reaction mixture, and the aqueous layerwas neutralized with dilute hydrochloric acid. The mixture was stirredat room temperature for 30 min, and then extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (12.99 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (150 ml). Tothe obtained solution was added hydroxylamine hydrochloride (10.10 g)and the mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(4-chloro-3-fluorophenyl)isoxazole-4-carboxylate (14.86 g, yield 76%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 76-77° C.

Reference Example 23

To a solution of ethyl5-(4-chloro-3-fluorophenyl)isoxazole-4-carboxylate (12.00 g) intetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 100 ml) at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give5-(4-chloro-3-fluorophenyl)-4-isoxazolylmethanol (9.73 g, yield 96%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 87-88° C.

Reference Example 24

A mixture of 4′-methoxyacetophenone (7.52 g), sodium hydride (60%, oil,2.00 g) and diethyl carbonate (100 ml) was stirred at 80° C. for 1 hr.Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.93 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.97 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(4-methoxyphenyl)isoxazole-4-carboxylate (9.48 g, yield 77%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 54-55° C.

Reference Example 25

To a solution of ethyl 5-(4-methoxyphenyl)isoxazole-4-carboxylate (8.56g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(4-methoxyphenyl)-4-isoxazolylmethanol (6.87 g, yield 97%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 57-58° C.

Reference Example 26

A mixture of 3′-bromo-4′-fluoroacetophenone (12.46 g), sodium hydride(60%, oil, 2.30 g) and diethyl carbonate (100 ml) was stirred at 80° C.for 1 hr. Water was added to the reaction mixture, and the aqueous layerwas neutralized with dilute hydrochloric acid. The mixture was stirredat room temperature for 30 min, and then extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (10.29 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (150 ml). Tothe obtained solution was added hydroxylamine hydrochloride (12.06 g)and the mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3-bromo-4-fluorophenyl)isoxazole-4-carboxylate (13.55 g, yield 75%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 111-112° C.

Reference Example 27

To a solution of ethyl 5-(3-bromo-4-fluorophenyl)isoxazole-4-carboxylate(10.01 g) in tetrahydrofuran (70 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 70 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(3-bromo-4-fluorophenyl)-4-isoxazolylmethanol (8.26 g, yield 95%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 134-135° C.

Reference Example 28

A mixture of 3′-bromo-4′-chloroacetophenone (6.27 g), sodium hydride(60%, oil, 1.06 g) and diethyl carbonate (90 ml) was stirred at 80° C.for 1 hr. Water was added to the reaction mixture, and the aqueous layerwas neutralized with dilute hydrochloric acid. The mixture was stirredat room temperature for 30 min, and then extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (4.84 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (3.75 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3-bromo-4-chlorophenyl)isoxazole-4-carboxylate (6.25 g, yield 70%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom diethyl ether-hexane. melting point: 109-110° C.

Reference Example 29

To a solution of ethyl 5-(3-bromo-4-chlorophenyl)isoxazole-4-carboxylate(6.19 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 40 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(3-bromo-4-chlorophenyl)-4-isoxazolylmethanol (5.10 g, yield 94%) as acolorless oil. NMR (CDCl₃) δ: 4.73 (2H, d, J=4.8 Hz), 7.59 (1H, d, J=8.4Hz), 7.72 (1H, dd, J=2.2, 8.4 Hz), 8.10 (1H, d, J=2.2 Hz), 8.37 (1H, s).

Reference Example 30

To a solution of 3-(5-phenyl-4-isoxazolyl)propan-1-ol (15.00 g) andtriethylamine (21.0 ml) in ethyl acetate (500 ml) was gently addedmethanesulfonyl chloride (9.0 ml) at 0° C., and the mixture was stirredat room temperature overnight. The reaction mixture was poured intodilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. A mixture of the residue, sodium cyanide (7.33g), sodium iodide (13.48 g) and N,N-dimethylformamide (150 ml) wasstirred at 70° C. for 5 hr. The reaction mixture was poured into waterand the mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried (MgSO₄) and concentrated.The residue was subjected to silica gel column chromatography, and4-(5-phenyl-4-isoxazolyl)butyronitrile (13.47 g, yield 86%) was obtainedas a colorless oil from a fraction eluted with ethyl acetate-hexane(1:2, volume ratio). NMR (CDCl₃) δ: 1.91-2.09 (2H, m), 2.36-2.46 (2H,m), 2.78-2.94 (2H, m), 7.44-7.58 (3H, m), 7.64-7.74 (2H, m), 8.22 (1H,s).

Reference Example 31

A mixture of 2′,4′-dichloroacetophenone (17.01 g), sodium hydride (60%,oil, 3.58 g) and diethyl carbonate (200 ml) was stirred at 80° C. for 1hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (16.23 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (200 ml). Tothe obtained solution was added hydroxylamine hydrochloride (12.53 g)and the mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(2,4-dichlorophenyl)isoxazole-4-carboxylate (17.51 g, yield 68%) wasobtained as a pale yellow oil from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). NMR (CDCl₃) δ: 1.24 (3H, t, J=7.0Hz), 4.25 (2H, q, J=7.0 Hz), 7.39 (1H, dd, J=1.8, 8.4 Hz), 7.46 (1H, d,J=8.4 Hz), 7.56 (1H, d, J=1.8 Hz), 8.67 (1H, s).

Reference Example 32

To a solution of ethyl 5-(2,4-dichlorophenyl)isoxazole-4-carboxylate(8.60 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 65 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(2,4-dichlorophenyl)-4-isoxazolylmethanol (7.09 g, yield 96%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 76-77° C.

Reference Example 33

A mixture of 3′,4′-dichloroacetophenone (8.64 g), sodium hydride (60%,oil, 1.83 g) and diethyl carbonate (100 ml) was stirred at 80° C. for 1hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.15 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (100 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.51 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3,4-dichlorophenyl)isoxazole-4-carboxylate (10.33 g, yield 79%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 117-118° C.

Reference Example 34

To a solution of ethyl 5-(3,4-dichlorophenyl)isoxazole-4-carboxylate(8.60 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 65 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give5-(3,4-dichlorophenyl)-4-isoxazolylmethanol (6.97 g, yield 95%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 101-102° C.

Reference Example 35

A mixture of 3′,5′-dichloroacetophenone (12.80 g), sodium hydride (60%,oil, 2.71 g) and diethyl carbonate (150 ml) was stirred at 80° C. for 1hr. Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (12.18 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (200 ml). Tothe obtained solution was added hydroxylamine hydrochloride (9.49 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(3,5-dichlorophenyl)isoxazole-4-carboxylate (12.48 g, yield 64%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 50-51° C.

Reference Example 36

To a solution of ethyl 5-(3,5-dichlorophenyl)isoxazole-4-carboxylate(10.82 g) in tetrahydrofuran (100 ml) was gently addeddiisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 100 ml) at0° C. and the mixture was stirred at room temperature for 30 min. Thereaction mixture was poured into dilute hydrochloric acid”, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated to give5-(3,5-dichlorophenyl)-4-isoxazolylmethanol (10.28 g, yield 94%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 104-105° C.

Reference Example 37

A mixture of 4′-phenylacetophenone (10.00 g), sodium hydride (60%, oil,1.96 g) and diethyl carbonate (150 ml) was stirred at 80° C. for 1 hr.Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (8.89 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (200 ml). Tothe obtained solution was added hydroxylamine hydrochloride (6.88 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and ethyl5-(4-phenylphenyl)isoxazole-4-carboxylate (10.98 g, yield 76%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 73-75° C.

Reference Example 38

To a solution of ethyl 5-(4-phenylphenyl)isoxazole-4-carboxylate (10.68g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 83.7 ml) at 0° C. and themixture was stirred at room temperature for 30 min. The reaction mixturewas poured into dilute hydrochloric acid, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried (MgSO₄) and concentrated to give5-(4-phenylphenyl)-4-isoxazolylmethanol (7.55 g, yield 83%) as colorlesscrystals. The crystals were recrystallized from ethyl acetate-hexane.melting point: 108-110° C.

Reference Example 39

To a solution of ethyl propiolate (7.50 g) in tetrahydrofuran (50 ml)was gently added a solution of pyrrolidine (6.4 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of3,4-dichloro-N-hydroxybenzenecarboxyimidoyl chloride (11.40 g) intetrahydrofuran (100 ml) at 0° C., and a solution of triethylamine (15ml) in tetrahydrofuran (10 ml) was gently added at 0° C. The mixture wasstirred at room temperature overnight and the reaction mixture waspoured into dilute hydrochloric acid. The mixture was extracted withethyl acetate and the ethyl acetate layer was washed with saturatedbrine, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography, and ethyl3-(3,4-dichlorophenyl)isoxazole-4-carboxylate (12.26 g, yield 84%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 129-130° C.

Reference Example 40

To a solution of ethyl 3-(3,4-dichlorophenyl)isoxazole-4-carboxylate(7.80 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 60 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give3-(3,4-dichlorophenyl)-4-isoxazolylmethanol (6.43 g, yield 96%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 103-104° C.

Reference Example 41

To a solution of ethyl propiolate (7.51 g) in tetrahydrofuran (50 ml)was gently added a solution of pyrrolidine (6.4 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of3-chloro-4-fluoro-N-hydroxybenzenecarboxyimidoyl chloride (10.20 g) intetrahydrofuran (100 ml) at 0° C. and then a solution of triethylamine(15 ml) in tetrahydrofuran (10 ml) was gently added at 0° C. The mixturewas stirred at room temperature overnight, the reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated. The residue was subjected to silica gelcolumn chromatography, and ethyl3-(3-chloro-4-fluorophenyl)isoxazole-4-carboxylate (10.93 g, yield 83%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 108-109° C.

Reference Example 42

To a solution of ethyl3-(3-chloro-4-fluorophenyl)isoxazole-4-carboxylate (9.70 g) intetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirredat room temperature for 30 min. The reaction mixture was poured intodilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give3-(3-chloro-4-fluorophenyl)-4-isoxazolylmethanol (7.91 g, yield 97%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 87-88° C.

Reference Example 43

To a solution of ethyl propiolate (8.61 g) in tetrahydrofuran (50 ml)was gently added a solution of pyrrolidine (7.4 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of4-chloro-3-fluoro-N-hydroxybenzenecarboxyimidoyl chloride (11.70 g) intetrahydrofuran (100 ml) at 0° C. and then a solution of triethylamine(16 ml) in tetrahydrofuran (10 ml) was gently added at 0° C. The mixturewas stirred at room temperature overnight, the reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated. The residue was subjected to silica gelcolumn chromatography, and ethyl3-(4-chloro-3-fluorophenyl)isoxazole-4-carboxylate (12.63 g, yield 83%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 77-78° C.

Reference Example 44

To a solution of ethyl3-(4-chloro-3-fluorophenyl)isoxazole-4-carboxylate (12.00 g) intetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 100 ml) at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give3-(4-chloro-3-fluorophenyl)-4-isoxazolylmethanol (9.75 g, yield 96%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 124-125° C.

Reference Example 45

To a solution of ethyl propiolate (6.13 g) in tetrahydrofuran (40 ml)was gently added a solution of pyrrolidine (5.2 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of3-bromo-4-fluoro-N-hydroxybenzenecarboxyimidoyl chloride (10.10 g) intetrahydrofuran (100 ml) at 0° C. and then a solution of triethylamine(1.1.5 ml) in tetrahydrofuran (10 ml) was gently added at 0° C. Themixture was stirred at room temperature overnight, the reaction mixturewas poured into dilute hydrochloric acid, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography, and ethyl3-(3-bromo-4-fluorophenyl)isoxazole-4-carboxylate (13.96 g, yield 71%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 96-97° C.

Reference Example 46

To a solution of ethyl 3-(3-bromo-4-fluorophenyl)isoxazole-4-carboxylate(10.47 g) in tetrahydrofuran (100 ml) was gently addeddiisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 75 ml) at 0°C. and the mixture was stirred at room temperature for 30 min. Thereaction mixture was poured into dilute hydrochloric acid, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated to give3-(3-bromo-4-fluorophenyl)-4-isoxazolylmethanol (9.75 g, yield 96%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 93-94° C.

Reference Example 47

A mixture of N-methoxy-N-methylamine hydrochloride (4.53 g),triethylamine (7.0 ml) and N,N-dimethylformamide (15 ml) was stirred atroom temperature for 30 min and 3-methyl-5-phenylisoxazole-4-carboxylicacid (8.26 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (6.58 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.33 g)were added. The mixture was stirred at room temperature overnight. Thereaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-methoxy-N-methyl-(3-methyl-5-phenyl-4-isoxazolyl)carbamide (13.95 g,yield 76%) was obtained as a pale yellow oil from a fraction eluted withethyl acetate-hexane (1:4, volume ratio). NMR (CDCl₃) δ: 2.36 (3H, s),3.20-3.60 (6H, m), 7.42-7.52 (3H, m), 7.72-7.84 (2H, m).

Reference Example 48

To a solution ofN-methoxy-N-methyl-(3-methyl-5-phenyl-4-isoxazolyl)carbamide (7.51 g) intetrahydrofuran (150 ml) was gently added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 70 ml) at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-methyl-5-phenylisoxazole-4-carbaldehyde (5.39 g,yield 94%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:4, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 87-88° C.

Reference Example 49

To a solution of ethyl propiolate (5.01 g) in tetrahydrofuran (50 ml)was gently added a solution of pyrrolidine (4.3 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of4-phenyl-N-hydroxybenzenecarboxyimidoyl chloride (9.28 g) intetrahydrofuran (100 ml) at 0° C. and then a solution of triethylamine(12.0 ml) in tetrahydrofuran (10 ml) was gently added at 0° C. Themixture was stirred at room temperature overnight, the reaction mixturewas poured into dilute hydrochloric acid, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography, and ethyl3-(4-phenylphenyl)isoxazole-4-carboxylate (13.04 g, yield 87%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 81-82° C.

Reference Example 50

To a solution of ethyl 3-(4-phenylphenyl)isoxazole-4-carboxylate (10.00g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixturewas stirred at room temperature for 30 min. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated to give3-(4-phenylphenyl)-4-isoxazolylmethanol (8.32 g, yield 97%) as colorlesscrystals. The crystals were recrystallized from ethyl acetate-hexane.melting point: 138-139° C.

Reference Example 51

A mixture of 3-(4-phenylphenyl)-4-isoxazolylmethanol (4.16 g) andthionyl chloride (10.0 ml) was stirred at 0° C. for 30 min. The reactionmixture was concentrated, and saturated aqueous sodium hydrogencarbonatewas added to the residue. The mixture was extracted with ethyl acetateand the ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The obtained colorless crystals were filtratedto give 4-chloromethyl-3-(4-phenylphenyl)isoxazole (3.84 g, yield 92%).The crystals were recrystallized from ethyl acetate-hexane. meltingpoint: 102-103° C.

Reference Example 52

To a solution of ethyl propiolate (5.00 g) in tetrahydrofuran (50 ml)was gently added a solution of pyrrolidine (4.3 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of4-trifluoromethyl-N-hydroxybenzenecarboxyimidoyl chloride (7.50 g) intetrahydrofuran (100 ml) at 0° C. and a solution of triethylamine (10.0ml) in tetrahydrofuran (10 ml) was gently added at 0° C. The mixture wasstirred at room temperature overnight, after which the reaction mixturewas poured into dilute hydrochloric acid, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography, and ethyl3-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (8.09 g, yield 85%)was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). NMR (CDCl₃) δ: 1.32 (3H, t, J=7.0Hz), 4.32 (2H, q, J=7.0 Hz), 7.70-7.78 (2H, m), 7.88-7.97 (2H, m), 9.05(1H, s).

Reference Example 53

To a solution of ethyl3-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (8.00 g) intetrahydrofuran (150 ml) was gently added diisobutylaluminum hydride(1.0 M tetrahydrofuran solution, 60 ml) at 0° C. and the mixture wasstirred at room temperature for 30 min. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (6.46 g, yield 95%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 70-71° C.

Reference Example 54

A mixture of 3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (6.00 g)and thionyl chloride (10.0 ml) was stirred at 0° C. for 30 min. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The obtained colorlesscrystals were filtrated to give4-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole (6.16 g, yield 95%).The crystals were recrystallized from ethyl acetate-hexane. meltingpoint: 84-85° C.

Reference Example 55

To a solution of methyl acetoacetate (8.88 g) and4-chloro-N-hydroxybenzenecarboxyimidoyl chloride (9.65 g) intetrahydrofuran (100 ml) was gently added a solution of triethylamine(15 ml) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred atroom temperature overnight, the reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio).

To a solution of the obtained colorless oil in tetrahydrofuran (100 ml)was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuransolution, 110 ml) at 0° C. and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated to give 3-(4-chlorophenyl)-5-methyl-4-isoxazolylmethanol(7.69 g, yield 68%) as colorless crystals. The crystals wererecrystallized from ethanol. melting point: 94-95° C.

Reference Example 56

A mixture of 3-(4-chlorophenyl)-5-methyl-4-isoxazolylmethanol (2.23 g)and thionyl chloride (5.0 ml) was stirred at 0° C. for 30 min. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The obtained colorlesscrystals were filtrated to give4-chloromethyl-3-(4-chlorophenyl)-5-methylisoxazole (2.20 g, yield 91%).The crystals were recrystallized from diisopropyl ether. melting point:91-92° C.

Reference Example 57

To a solution of methyl acetoacetate (8.88 g) and4-trifluoromethyl-N-hydroxybenzenecarboxyimidoyl chloride (11.35 g) intetrahydrofuran (100 ml) was gently added a solution of triethylamine(15 ml) in tetrahydrofuran (10 ml) at 0° C. and the mixture was stirredat room temperature overnight. The reaction mixture was poured intodilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio).

To a solution of the obtained colorless oil in tetrahydrofuran (100 ml)was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuransolution, 110 ml) at 0° C. and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated to give5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (7.86 g, yield60%) as colorless crystals. The crystals were recrystallized fromdiisopropyl ether-hexane. melting point: 72-73° C.

Reference Example 58

A mixture of 5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol(1.75 g) and thionyl chloride (5.0 ml) was stirred at 0° C. for 30 min.The reaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The obtained colorlesscrystals were filtrated to give4-chloromethyl-5-methyl-3-(4-trifluoromethylphenyl)isoxazole (1.50 g,yield 80%). The crystals were recrystallized from diisopropyl ether.melting point: 91-92° C.

Reference Example 59

To a solution of ethyl5-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (7.63 g) intetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride(1.0 M hexane solution, 59 ml) at 0° C. and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated to give 5-(4-trifluoromethylphenyl)-4-isoxazolylmethanol(6.29 g, yield 97%) as colorless crystals. The crystals wererecrystallized from ethyl acetate-hexane to give a colorless prism.melting point: 106-107° C.

Reference Example 60

To a mixture of 5-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (5.65g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwisethionyl chloride (4.15 g) at 0° C. and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was concentrated, saturatedaqueous sodium hydrogencarbonate was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. Theobtained colorless crystals were filtrated and recrystallized from ethylacetate-hexane to give4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (4.70 g, yield 77%)as a colorless prism. melting point: 99-100° C.

Reference Example 61

A mixture of 2′,4′-difluoroacetophenone (9.50 g), sodium hydride (60%,oil, 2.44 g) and diethyl carbonate (80 ml) was stirred for 1.5 hr at 80°C. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. A mixture of the residue andN,N-dimethylformamide dimethylacetal (7.25 g) was refluxed for 1 hr. Thereaction mixture was concentrated, and the residue was dissolved inethanol (60 ml). To the obtained solution was added hydroxylaminehydrochloride (6.34 g) and the mixture was refluxed for 2 hr. Thereaction mixture was concentrated, water was added to the residue andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried (MgSO₄) and concentrated. Theresidue was subjected to silica gel column chromatography, and ethyl5-(2,4-difluorophenyl)isoxazole-4-carboxylate (3.85 g, yield 35%) wasobtained as an oil from a fraction eluted with ethyl acetate-hexane(1:9, volume ratio). NMR (CDCl₃) δ: 1.29 (3H, t, J=7.0 Hz), 4.29 (2H, q,J=7.0 Hz), 6.9-7.1 (2H, m) 7.6-7.75 (1H, m), 8.66 (1H, s).

Reference Example 62

To a solution of ethyl 5-(2,4-difluorophenyl)isoxazole-4-carboxylate(3.85 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 33 ml) at 0° C. and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 5-(2,4-difluorophenyl)-4-isoxazolylmethanol (2.70 g,yield 84%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane to give a colorless prism.melting point: 60-61° C.

Reference Example 63

To a solution of 5-(2,4-difluorophenyl)-4-isoxazolylmethanol (2.50 g) intoluene (50 ml) was added dropwise thionyl chloride (2.11 g) at 0° C.,and the mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and 4-chloromethyl-5-(2,4-difluorophenyl)isoxazole (2.20g, yield 81%) was obtained as an oil from a fraction eluted with ethylacetate-hexane (1:5, volume ratio). NMR (CDCl₃) δ: 4.53 (2H, s),6.95-7.15 (2H, m), 7.6-7.75 (1H, m), 8.43 (1H, s).

Reference Example 64

A mixture of 2-acetyl-5-chlorothiophene (10.0 g), sodium hydride (60%,oil, 2.49 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 30min. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and ethyl 3-(5-chloro-2-thienyl)-3-oxopropionate wasobtained as an oil from a fraction eluted with ethyl acetate-hexane(1:5, volume ratio). A mixture of this oil and N,N-dimethylformamidedimethylacetal (11.1 g) was refluxed for 1 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethanol (80 ml). To theobtained solution was added hydroxylamine hydrochloride (8.65 g), andthe mixture was refluxed for 2 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and the crystals obtainedfrom a fraction eluted with ethyl acetate-hexane (1:5, volume ratio)were recrystallized from ethyl acetate-hexane to give ethyl5-(5-chloro-2-thienyl)isoxazole-4-carboxylate (9.34 g, yield 58%) as acolorless prism. melting point: 74-75° C.

Reference Example 65

To a solution of ethyl 5-(5-chloro-2-thienyl)isoxazole-4-carboxylate(9.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.5 M toluene solution, 52 ml) at 0° C. and the mixture wasstirred at room temperature for 1.5 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the precipitated5-(5-chloro-2-thienyl)-4-isoxazolylmethanol (7.00 g, yield 93%) wasfiltrated and recrystallized from ethyl acetate-hexane to give acolorless needle. melting point: 80-81° C.

Reference Example 66

To a mixture of 5-(5-chloro-2-thienyl)-4-isoxazolylmethanol (6.54 g),tetrahydrofuran (20 ml) and toluene (100 ml) was added dropwise thionylchloride (5.41 g) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was concentrated, saturatedaqueous sodium hydrogencarbonate was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and crystals of4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.98 g, yield 98%) wereobtained from a fraction eluted with ethyl acetate-hexane (1:5, volumeratio) and recrystallized from ethyl acetate-hexane to give a colorlessprism. melting point: 70-71° C.

Reference Example 67

A mixture of 4′-chloro-3′-methylacetophenone (10.0 g), sodium hydride(60%, oil, 2.38 g) and diethyl carbonate (80 ml) was stirred for 90 minat 80° C. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and ethyl 3-(4-chloro-3-methylphenyl)-3-oxopropionatewas obtained as an oil from a fraction eluted with ethyl acetate-hexane(1:9, volume ratio). A mixture of this oil and N,N-dimethylformamidedimethylacetal (10.6 g) was refluxed for 1 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethanol (80 ml). To theobtained solution was added hydroxylamine hydrochloride (8.24 g), andthe mixture was refluxed for 2 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and crystals of ethyl5-(4-chloro-3-methylphenyl)isoxazole-4-carboxylate (9.26 g, yield 59%)were obtained from a fraction eluted with ethyl acetate-hexane (1:5,volume ratio) and recrystallized from hexane to give a colorless prism.melting point: 50-51° C.

Reference Example 68

To a solution of ethyl5-(4-chloro-3-methylphenyl)isoxazole-4-carboxylate (8.50 g) intetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride(1.5 M toluene solution, 47 ml) at 0° C., and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated to give 5-(4-chloro-3-methylphenyl)-4-isoxazolylmethanol(6.13 g, yield 86%) as colorless crystals, which were recrystallizedfrom ethyl acetate-hexane to give a colorless needle. melting point:92-93° C.

Reference Example 69

To a mixture of 5-(4-chloro-3-methylphenyl)-4-isoxazolylmethanol (5.80g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwisethionyl chloride (4.63 g) at 0° C. and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated, saturatedaqueous sodium hydrogencarbonate was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. Theobtained colorless crystals were filtrated and recrystallized from ethylacetate-hexane to give4-chloromethyl-5-(4-chloro-3-methylphenyl)isoxazole (5.47 g, yield 87%)as a colorless prism. melting point: 84-85° C.

Reference Example 70

A mixture of 2′,5′-dichloroacetophenone (10.0 g), sodium hydride (60%,oil, 2.12 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 20min. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and ethyl 3-(2,5-dichlorophenyl)-3-oxopropionate wasobtained as an oil from a fraction eluted with ethyl acetate-hexane(1:9, volume ratio). A mixture of this oil and N,N-dimethylformamidedimethylacetal (9.46 g) was refluxed for 1 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethanol (80 ml). To theobtained solution was added hydroxylamine hydrochloride (7.35 g), andthe mixture was refluxed for 2 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and ethyl5-(2,5-dichlorophenyl)isoxazole-4-carboxylate (6.40 g, yield 42%) wasobtained as an oil from a fraction eluted with ethyl acetate-hexane(1:5, volume ratio). NMR (CDCl₃) δ: 1.23 (3H, t, J=7 Hz), 4.25 (2H, q,J=7 Hz), 7.4-7.6 (3H, m), 8.68 (1H, s).

Reference Example 71

To a solution of ethyl 5-(2,5-dichlorophenyl)isoxazole-4-carboxylate(6.40 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.5 M toluene solution, 33 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 5-(2,5-dichlorophenyl)-4-isoxazolylmethanol (3.86,yield 71%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio) and recrystallized fromisopropyl ether-hexane to give a colorless prism. melting point: 51-52°C.

Reference Example 72

To a solution of 5-(2,5-dichlorophenyl)-4-isoxazolylmethanol (3.80 g) intoluene (60 ml) was added dropwise thionyl chloride (2.78 g) at 0° C.and the mixture was stirred at room temperature for 2 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and 4-chloromethyl-5-(2,5-dichlorophenyl)isoxazole (2.15g, yield 53%) was obtained as an oil from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). NMR (CDCl₃) δ: 4.45 (2H, s),7.4-7.55 (3H, m), 8.48 (1H, s).

Reference Example 73

A mixture of 4′-methylthioacetophenone (20.0 g), sodium hydride (60%,oil, 4.81 g) and diethyl carbonate (120 ml) was stirred at 80° C. for1.5 hr. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and ethyl 3-(4-methylthiophenyl)-3-oxopropionate wasobtained as an oil from a fraction eluted with ethyl acetate-hexane(1:9, volume ratio). A mixture of this oil and N,N-dimethylformamidedimethylacetal (21.5 g) was refluxed for 1 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethanol (80 ml). To theobtained solution was added hydroxylamine hydrochloride (16.7 g), andthe mixture was refluxed for 2 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and the crystals obtainedfrom a fraction eluted with ethyl acetate-hexane (1:5, volume ratio)were recrystallized from ethyl acetate-hexane to give crystals of ethyl5-(4-methylthiophenyl)isoxazole-4-carboxylate (18.9 g, yield 60%).melting point: 59-60° C.

Reference Example 74

To a solution of ethyl 5-(4-methylthiophenyl)isoxazole-4-carboxylate(10.0 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (0.95 M hexane solution, 92 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The obtained crystals were recrystallized fromethyl acetate-isopropyl ether to give5-(4-methylthiophenyl)-4-isoxazolylmethanol (7.50 g, yield 89%) as acolorless prism. melting point: 102-103° C.

Reference Example 75

To a mixture of 5-(4-methylthiophenyl)-4-isoxazolylmethanol (7.35 g),tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionylchloride (5.93 g) at 0° C. and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated, saturatedaqueous sodium hydrogencarbonate was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.70 g, yield 97%) wasobtained as crystals from a fraction eluted with ethyl acetate-hexane(1:3, volume ratio) and recrystallized from diethyl ether-hexane to givea colorless prism. melting point: 73-74° C.

Reference Example 76

A mixture of 4′-methylacetophenone (15.4 g), sodium hydride (60%, oil,4.59 g) and diethyl carbonate (80 ml) was stirred at 80° C. for 30 min.Water was added to the reaction mixture, and the mixture was neutralizedwith dilute hydrochloric acid and extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (20.5 g) was refluxed for 1 hr. The reaction mixture wasconcentrated, and the residue was dissolved in ethanol (120 ml). To theobtained solution was added hydroxylamine hydrochloride (16.0 g), andthe mixture was refluxed for 2 hr. The reaction mixture wasconcentrated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and ethyl5-(4-methylphenyl)isoxazole-4-carboxylate (17.2 g, yield 65%) wasobtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio) and recrystallized from hexane togive a colorless prism. melting point: 45-46° C.

Reference Example 77

To a solution of ethyl 5-(4-methylphenyl)isoxazole-4-carboxylate (7.70g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M toluene solution, 83 ml) at 0° C. and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in toluene (100 ml)and thionyl chloride (5.94 g) was added dropwise at 0° C., after whichthe mixture was stirred at room temperature for 1 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and 4-chloromethyl-5-(4-methylphenyl)isoxazole (6.49 g,yield 94%) was obtained as an oil from a fraction eluted with ethylacetate-hexane (1:9, volume ratio). NMR (CDCl₃) δ: 2.44 (3H, s), 4.62(2H, s), 7.34 (2H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz), 8.35 (1H, s).

Reference Example 78

A mixture of 2-acetyl-4,5-dichlorothiophene (6.10 g), sodium hydride(60%, oil, 1.25 g) and diethyl carbonate (60 ml) was stirred at 80° C.for 30 min. Water was added to the reaction mixture, and the mixture wasneutralized with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and an oil was obtained from a fraction eluted withethyl acetate-hexane (1:9, volume ratio). A mixture of the oil andN,N-dimethylformamide dimethylacetal (5.60 g) was refluxed for 1 hr. Thereaction mixture was concentrated, and the residue was dissolved inethanol (80 ml). To the obtained solution was added hydroxylaminehydrochloride (4.35 g) and the mixture was refluxed for 1.5 hr. Thereaction mixture was concentrated, water was added to the residue andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried (MgSO₄) and concentrated. Theresidue was subjected to silica gel column chromatography, and ethyl5-(4,5-dichloro-2-thienyl)isoxazole-4-carboxylate (3.42 g, yield 37%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:9, volume ratio) and recrystallized from ethyl acetateto give a pale-yellow prism. melting point: 120-121° C.

Reference Example 79

To a solution of ethyl 5-(4,5-dichloro-2-thienyl)isoxazole-4-carboxylate(3.30 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminumhydride (0.95 M hexane solution, 29.7 ml) at 0° C. and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in toluene (60 ml),thionyl chloride (2.02 g) was added dropwise at 0° C., and the mixturewas stirred at room temperature for 1 hr. The reaction mixture wasconcentrated, saturated aqueous sodium hydrogencarbonate was added tothe residue, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 4-chloromethyl-5-(4,5-dichloro-2-thienyl)isoxazole(2.41 g, yield 79%) was obtained as crystals from a fraction eluted withethyl acetate-hexane (1:9, volume ratio) and recrystallized from hexaneto give a colorless prism. melting point: 60-61° C.

Reference Example 80

A mixture of 4-nitrobenzylbromide (15.0 g) and triisopropyl phosphite(15.9 g) was stirred for 3 hr while heating under reflux. The reactionmixture was subjected to silica gel column chromatography, anddiisopropyl 4-nitrobenzylphosphonate (19.5 g) was obtained as an oilfrom a fraction eluted with ethyl acetate-chloroform (1:1, volumeratio). A mixture of this oil, 5% palladium-carbon (2.3 g) and ethanol(130 ml) was stirred at room temperature for 6 hr under a hydrogenatmosphere. The catalyst was filtered off and the filtrate (ethanolsolution) was concentrated to give diisopropyl 4-aminobenzylphosphonate(17.2 g, yield 98%) as a yellow oil.

NMR (CDCl₃) δ: 1.17 (6H, d, J=7 Hz), 1.27 (6H, d, J=7 Hz) 2.92 (2H,brs), 3.25 (2H, d, J=22 Hz), 4.55-4.65 (2H, m), 6.64 (2H, d, J=8 Hz),7.09 (2H, dd, J=3/9 Hz).

In the same manner as in Reference Example 1, the following compoundswere synthesized.

Reference Example 81 dibutyl 4-aminobenzylphosphonate

yield 98% (yellow oil)

NMR (CDCl₃) δ: 0.90 (6H, t, J=7 Hz), 1.25-1.45 (4H, m), 1.5-1.65 (4H,m), 2.87 (2H brs), 3.04 (2H, d, J=22 Hz), 3.9-4.05 (4H, m), 6.66 (2H, d,J=8 Hz), 7.08 (2H, dd, J=3/9 Hz).

Reference Example 82 diethyl 4-amino-3-methylbenzylphosphonate

yield 97% (yellow oil)

NMR (CDCl₃) δ: 1.25 (6H, t, J=7 Hz), 2.16 (3H, s), 3.03 (2H, d, J=21Hz), 3.18 (2H, s), 3.95-4.05 (4H, m), 6.66 (2H, d, J=8 Hz), 6.95-7.0(2H, m).

Reference Example 83

To a mixture of titanium tetrachloride (20.0 g) and tetrahydrofuran (100ml) were added 4-nitrobenzaldehyde (8.00 g) and ethyldiethylphosphonoacetate (11.9 g) under ice-cooling, andN-methylmorpholine (21.4 g) was added. The mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into water and themixture was extracted with ethyl acetate. The ethyl acetate layer wasconcentrated to give crystals of4-[(E)-2-(diethylphosphono)-2-ethoxycarbonylethenyl]nitrobenzene (15.7g, yield 83%), which were recrystallized from dichloromethane-isopropylether to give a colorless prism (14.0 g). melting point: 60-61° C. Amixture of this compound (5.00 g), iron (3.13 g), conc. hydrochloricacid (7 ml) and ethanol (30 ml) was stirred at room temperature for 30min. The reaction mixture was poured into water and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was concentrated,and the residue was subjected to silica gel column chromatography togive crystals of4-[(E)-2-(diethylphosphono)-2-ethoxycarbonylethenyl]aniline (2.40 g,yield 52%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v),which were recrystallized from acetone-isopropyl ether to give a paleyellow needle (1.75 g). melting point: 79-80° C.

Elemental analysis:

Calculated (C₁₅H₂₂NO₅P) C, 55.04; H, 6.77; N, 4.29. Found C, 55.07; H,6.92; N, 4.25.

Example 1

To a solution of 5-(4-trifluoromethoxyphenyl)-4-isoxazolylmethanol (5.60g) in toluene (100 ml) was added dropwise thionyl chloride (2.36 ml) at0° C. and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml) and added to a mixture of diethylmalonate (6.92 g), sodium hydride (60%, oil, 1.72 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (70 ml) and acetic acid (70 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionic acid (3.77g, yield 58%). The crystals were recrystallized from acetone-hexane.melting point: 116-118° C.

Example 2

A mixture of 3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionic acid(3.30 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionate (2.80 g, yield81%) was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). NMR (CDCl₃) δ: 2.66 (2H, t, J=7.4Hz), 2.99 (2H, q, J=7.4 Hz), 3.69 (3H, s), 7.35 (2H, dd, J=1.0, 9.2 Hz),7.76 (2H, d, J=9.2 Hz), 8.24 (1H, s).

Example 3

To a solution of methyl3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionate (1.63 g) intetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 13.2 ml) at 0° C., and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propan-1-ol (1.36 g, yield92%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 50-51° C.

Example 4

A mixture of 3-[5-(4-bromophenyl)-4-isoxazolyl]propan-1-ol (1.10 g),copper cyanide (1.41 g), tris(dibenzylideneacetone)dipalladium (130 mg),1,1′-bis(diphenylphosphino)ferrocene (314 mg), tetraethylammoniumcyanide (553 mg) and 1,4-dioxane (20 ml) was refluxed for 3.5 hr. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated. The residue was subjected to silica gelcolumn chromatography, and 3-[5-(4-cyanophenyl)-4-isoxazolyl]propan-1-ol(418 mg, yield 52%) was obtained as pale yellow crystals from a fractioneluted with ethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 82-83° C.

Example 5

To a solution of ethyl propiolate (6.13 g) in tetrahydrofuran (40 ml)was gently added a solution of pyrrolidine (5.2 ml) in tetrahydrofuran(5 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. To theobtained mixture was added a solution of4-chloro-N-hydroxybenzenecarboxyimidoyl chloride (7.60 g) intetrahydrofuran (100 ml) at 0° C., and a solution of triethylamine (11.5ml) in tetrahydrofuran (10 ml) was gently added at 0° C. The mixture wasstirred at room temperature overnight, poured into dilute hydrochloricacid, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio).

To a solution of the obtained colorless oil in tetrahydrofuran (100 ml)was gently added diisobutylaluminum hydride (1.0 M hexane solution, 85ml) at 0° C. and the mixture was stirred at room temperature for 30 min.The reaction mixture was poured into dilute hydrochloric acid, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated to give acolorless oil. To a solution of the obtained colorless oil in toluene(100 ml) was added dropwise thionyl chloride (4.50 ml) at 0° C., and themixture was stirred at room temperature for 3 hr. The reaction mixturewas concentrated, saturated aqueous sodium hydrogencarbonate was addedto the residue, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was dissolved in tetrahydrofuran (100 ml), andadded to a mixture of diethyl malonate (12.81 g), sodium hydride (60%,oil, 3.20 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (4.93 g, yield 49%).The crystals were recrystallized from isopropyl ether. melting point:149-150° C.

Example 6

To a solution of 5-(3-bromo-4-chlorophenyl)-4-isoxazolylmethanol (5.09g) in toluene (100 ml) was added dropwise thionyl chloride (1.93 ml) at0° C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (50 ml), and added to a mixture of diethylmalonate (5.64 g), sodium hydride (60%, oil, 1.41 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionic acid (3.24 g,yield 56%). The crystals were recrystallized from diethyl ether-hexane.melting point: 177-180° C.

Example 7

A mixture of ethyl benzoylacetate (12.65 g) and N,N-dimethylformamidedimethylacetal (11.80 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (200 ml). Tothe obtained solution was added hydroxylamine hydrochloride (9.18 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and a yellow oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:2, volumeratio). To a solution of the obtained yellow oil in tetrahydrofuran (100ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution,100 ml) at 0° C. and the mixture was stirred at room temperature for 30min. The reaction mixture was poured into dilute hydrochloric acid, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried (MgSO₄) and concentrated. To asolution of the residue in toluene (100 ml) was added dropwise thionylchloride (5.0 ml) at 0° C., and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated, saturatedaqueous sodium hydrogencarbonate was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas dissolved in tetrahydrofuran (100 ml) and added to a mixture ofdiethyl malonate (13.50 g), sodium hydride (60%, oil, 3.33 g) andtetrahydrofuran (30 ml) at 0° C. The mixture was stirred at 0° C. for 1hr and then at room temperature overnight. The reaction mixture wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-(5-phenyl-4-isoxazolyl)propionic acid (9.14 g, yield 64%). Thecrystals were recrystallized from isopropyl ether. melting point: 90-91°C.

Example 8

A mixture of 4′-chloroacetophenone (10.47 g), sodium hydride (60%, oil,2.71 g) and diethyl carbonate (150 ml) was stirred at 80° C. for 1 hr.Water was added to the reaction mixture, and the aqueous layer wasneutralized with dilute hydrochloric acid. The mixture was stirred atroom temperature for 30 min, and then extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A mixture of the residue and N,N-dimethylformamidedimethylacetal (12.18 g) was refluxed for 1.5 hr. The reaction mixturewas concentrated, and the residue was dissolved in ethanol (200 ml). Tothe obtained solution was added hydroxylamine hydrochloride (9.49 g) andthe mixture was refluxed for 5 hr. The reaction mixture wasconcentrated, dilute hydrochloric acid was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel column chromatography, and a yellow oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:2, volumeratio). To a solution of the obtained yellow oil in tetrahydrofuran (100ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution,100 ml) at 0° C., and the mixture was stirred at room temperature for 30min. The reaction mixture was poured into dilute hydrochloric acid, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried (MgSO₄) and concentrated. To asolution of the residue in toluene (100 ml) was added dropwise thionylchloride (2.7 ml) at 0° C., and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated, saturatedaqueous sodium hydrogencarbonate was added to the residue, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. The residuewas dissolved in tetrahydrofuran (100 ml) and added to a mixture ofdiethyl malonate (7.96 g), sodium hydride (60%, oil, 1.95 g) andtetrahydrofuran (30 ml) at 0° C. The mixture was stirred at 0° C. for 1hr and then at room temperature overnight. The reaction mixture wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (7.84 g, yield46%). The crystals were recrystallized from isopropyl ether. meltingpoint: 155-154° C.

Example 9

To a solution of methyl3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionate (1.00 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 6.5 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propan-1-ol (0.85 g, yield92%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 75-76° C.

Example 10

To a solution of diethyl malonate (4.71 g) in tetrahydrofuran (40 ml)was gradually added sodium hydride (60%, oil, 1.07 g) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (3.50 g) intetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 15 hr. The reaction mixture was pouredinto water, acidified with 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in a mixture of 6Nhydrochloric acid (40 ml) and acetic acid (60 ml) and heated underreflux for 8 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated,dried and recrystallized from ethyl acetate to give a colorless prism(3.00 g, yield 79%) of3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid. meltingpoint: 171-172° C.

Example 11

To a solution of 5-(4-fluorophenyl)-4-isoxazolylmethanol (5.84 g) intoluene (50 ml) was added dropwise thionyl chloride (3 ml) at 0° C., andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (6.92 g), sodium hydride(60%, oil, 1.70 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(30 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (4.53 g, yield 78%).The crystals were recrystallized from isopropyl ether. melting point:126-127° C.

Example 12

To a solution of diethyl malonate (11.0 g) in tetrahydrofuran (60 ml)was gradually added sodium hydride (60%, oil, 2.50 g) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(4-methylphenyl)isoxazole (6.48 g) in tetrahydrofuran(80 ml) was added dropwise at 0° C. The mixture was stirred at roomtemperature for 15 hr. The reaction mixture was poured into 2Nhydrochloric acid and the mixture was extracted with ethyl acetate. Theethyl acetate layer was concentrated and the residue was dissolved in amixture of 6N hydrochloric acid (80 ml) and acetic acid (120 ml). Themixture was heated under reflux for 8 hr. The reaction mixture wasconcentrated, and water was added to the residue. The obtained colorlesscrystals were filtrated, dried and recrystallized from ethylacetate-hexane to give a colorless prism (5.03 g, yield 70%) of3-[5-(4-methylphenyl)-4-isoxazolyl]propionic acid. melting point:121-122° C.

Example 13

To a solution of 5-(4-methoxyphenyl)-4-isoxazolylmethanol (6.09 g) intoluene (100 ml) was added dropwise thionyl chloride (3.3 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (9.51 g), sodium hydride(60%, oil, 2.32 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionic acid (5.16 g, yield 70%).The crystals were recrystallized from isopropyl ether-diethyl ether.melting point: 101-102° C.

Example 14

A mixture of diethyl 4-aminobenzylphosphonate (0.37 g),3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.35 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.25 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-diethylphosphonomethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide(0.61 g, yield 92%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 138-139° C.

Example 15

A mixture of 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (6.57 g),conc. sulfuric acid (0.5 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionate(6.51 g, yield 94%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 51-52° C.

Example 16

To a solution of methyl 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionate(6.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 50 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(4-chlorophenyl)-4-isoxazolyl]propan-1-ol (4.89g, yield 91%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 58-59° C.

Example 17

A mixture of diethyl 4-aminobenzylphosphonate (0.76 g),3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.66 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.49 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-diethylphosphonomethylphenyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide(1.14 g, yield 91%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 88-90° C.

Example 18

To a mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (1.28g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethylchlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20°C. for 1 hr. To the obtained mixture was added aqueous ammonia (15 ml)and the mixture was stirred at room temperature for 1 hr. The reactionmixture was poured into water and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with dilute hydrochloricacid, saturated aqueous sodium hydrogencarbonate and then saturatedbrine, dried (MgSO₄) and concentrated to give3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.91 g, yield 71%) ascolorless crystals. The crystals were recrystallized fromacetone-hexane. melting point: 158-159° C.

Example 19

A mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (4.05 g),conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionate(3.93 g, yield 92%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 56-57° C.

Example 20

A mixture of 3-trifluoromethylbenzylamine (0.75 ml),3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.90 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.82 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(3-trifluoromethylbenzyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide(1.27 g, yield 87%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from isopropyl ether-hexane. melting point: 80-81° C.

Example 21

A mixture of diethyl 4-aminobenzylphosphonate (1.25 g),3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.80 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide(1.89 g, yield 93%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 139-140° C.

Example 22

To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.08 g),triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethylchlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20°C. for 1 hr. To the obtained mixture was added aqueous ammonia (20 ml),and the mixture was stirred at room temperature for 1 hr. The reactionmixture was poured into water and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with dilute hydrochloricacid, saturated aqueous sodium hydrogencarbonate and then saturatedbrine, dried (MgSO₄) and concentrated to give3-(5-phenyl-4-isoxazolyl)propionamide (0.82 g, yield 78%) as colorlesscrystals. The crystals were recrystallized from ethyl acetate-hexane.melting point: 151-152° C.

Example 23

To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g),triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethylchlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20°C. for 1 hr. To the obtained mixture was added aqueous ethylaminesolution (10 ml), and the mixture was stirred at room temperature for 1hr. The reaction mixture was poured into water and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withdilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate andthen saturated brine, dried (MgSO₄) and concentrated to giveN-ethyl-3-(5-phenyl-4-isoxazolyl)propionamide (0.93 g, yield 83%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 75-76° C.

Example 24

A mixture of ethyl (E)-3-(5-phenyl-4-isoxazolyl)propenoate (4.89 g), 2Nhydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 3 hr.The reaction mixture was concentrated, and water was added to theresidue. The obtained colorless crystals were filtrated to give(E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (4.02 g, yield 93%). Thecrystals were recrystallized from acetone-hexane. melting point:197-199° C.

Example 25

To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.97 g),triethylamine (1 ml) and tetrahydrofuran (60 ml) was added ethylchlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20°C. for 1 hr. To the obtained mixture was added aqueous ammonia (1 ml),and the mixture was stirred at room temperature for 1 hr. The reactionmixture was poured into water and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with dilute hydrochloricacid, saturated aqueous sodium hydrogencarbonate and then saturatedbrine, dried (MgSO₄) and concentrated to give(E)-3-(5-phenyl-4-isoxazolyl)propenamide (0.86 g, yield 89%) ascolorless crystals. The crystals were recrystallized fromacetone-hexane. melting point: 194-196° C.

Example 26

A mixture of diethyl 4-aminobenzylphosphonate (0.83 g),(E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.69 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.54 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.65 g) andN,N-dimethylformamide (30 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and(E)-N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propenamide(0.86 g, yield 61%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 173-174° C.

Example 27

To a mixture of (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (0.76 g),triethylamine (0.8 ml) and tetrahydrofuran (50 ml) was added ethylchlorocarbonate (0.4 ml) at −30° C. and the mixture was stirred at −20°C. for 1 hr. To the obtained mixture was added aqueous ethylaminesolution (1 ml), and the mixture was stirred at room temperature for 1hr. The reaction mixture was poured into water and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withdilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate andthen saturated brine, dried (MgSO₄) and concentrated to give(E)-N-ethyl-3-(5-phenyl-4-isoxazolyl)propenamide (0.78 g, yield 91%) ascolorless crystals. The crystals were recrystallized fromacetone-hexane. melting point: 156-157° C.

Example 28

To a mixture of 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.95g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethylchlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20°C. for 1 hr. To the obtained mixture was added aqueous ammonia (5 ml),and the mixture was stirred at room temperature for 1 hr. The reactionmixture was poured into water and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with dilute hydrochloricacid, saturated aqueous sodium hydrogencarbonate and then saturatedbrine, dried (MgSO₄) and concentrated to give3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 91%) ascolorless crystals. The crystals were recrystallized from ethylacetate-hexane. melting point: 149-151° C.

Example 29

A mixture of methyl 4-aminobenzoate (0.47 g),3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.60 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.50 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide(0.75 g, yield 79%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 140-141° C.

Example 30

A mixture of N-diphenylmethylpiperazine (0.85 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-diphenylmethyl-N′-[3-(5-phenyl-4-isoxazolyl)propionyl]piperazine (1.35g, yield 93%) was obtained as a colorless oil from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ: 2.26-2.42(4H, m), 2.50-2.64 (2H, m), 2.94-3.08 (2H, m), 3.32-3.44 (2H, m),3.56-3.68 (2H, m), 4.22 (1H, s), 7.12-7.54 (13H, m), 7.66-7.86 (2H, m),8.21 (1H, s).

Example 31

A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.75 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.72 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-(4-chlorophenyl)-2-thiazolyl]-3-(5-phenyl-4-isoxazolyl)propionamide(0.58 g, yield 43%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 172-173° C.

Example 32

A mixture of methyl 4-aminobenzoate (0.46 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.60 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.48 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-methoxycarbonylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.86g, yield 89%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 111-112° C.

Example 33

A mixture of 2-amino-5-methyl-4-phenylthiazole (0.95 g),3-(5-phenyl-4-isoxazolyl)propionic acid (1.01 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.78 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(5-methyl-4-phenyl-2-thiazolyl)-3-(5-phenyl-4-isoxazolyl)propionamide(1.74 g, yield 96%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 150-151° C.

Example 34

A mixture of 2-aminoquinoline (0.55 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.82 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(2-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.09 g, yield 84%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:1, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 112-113° C.

Example 35

A mixture of 4-aminobenzamide (0.55 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.87 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.88 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-carbamoylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g,yield 71%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from tetrahydrofuran-hexane. melting point: 250-251° C.

Example 36

A mixture of 3-(2-aminoethyl)indole hydrochloride (0.46 g),triethylamine (0.6 ml) and N,N-dimethylformamide (20 ml) was stirred atroom temperature for 1 hr. To the obtained mixture was added3-(5-phenyl-4-isoxazolyl)propionic acid (0.42 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g),and the mixture was stirred at room temperature overnight. The reactionmixture was poured into water and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with dilute hydrochloricacid, saturated aqueous sodium hydrogencarbonate and then saturatedbrine, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography, andN-[2-(3-indolyl)ethyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.63 g,yield 91%) was obtained as a colorless oil from a fraction eluted withethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ: 2.32-2.44 (2H,m), 2.88-3.04 (4H, m), 3.54-3.66 (2H, m), 5.45 (1H, br s), 6.93 (1H, d,J=2.2 Hz), 7.04-7.28 (2H, m), 7.32-7.62 (5H, m), 7.64-7.74 (2H, m), 8.05(1H, br s), 8.17 (1H, s).

Example 37

A mixture of diethyl 4-aminobenzylphosphonate (1.20 g),5-phenyl-4-isoxazolylacetic acid (0.84 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-diethylphosphonomethylphenyl)-5-phenyl-4-isoxazolylacetamide (1.58g, yield 89%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 132-133° C.

Example 38

A mixture of 2-amino-4-(4-chlorophenyl)thiazole (0.65 g),5-phenyl-4-isoxazolylacetic acid (0.60 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.51 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.59 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-(4-chlorophenyl)-2-thiazolyl]-5-phenyl-4-isoxazolylacetamide (0.92g, yield 79%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 210-211° C.

Example 39

A mixture of ethyl 4-aminophenylacetate (0.32 g),3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.37 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.28 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature 0.159overnight. The reaction mixture was poured into water and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith dilute hydrochloric acid, saturated aqueous sodiumhydrogencarbonate and then saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, andN-(4-ethoxycarbonylmethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide(0.56 g, yield 93%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 117-118° C.

Example 40

A mixture of 3-aminopyridine (0.18 g),3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.50 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(3-pyridyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.60 g,yield 96%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from acetone-hexane. melting point: 197-198° C.

Example 41

A mixture of 5-amino-2-(2-methyl-1-imidazolyl)pyridine (0.40 g),3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.58 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.45 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.54 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[6-(2-methyl-1-imidazolyl)-3-pyridyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide(0.59 g, yield 63%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from acetone-hexane. melting point: 193-194° C.

Example 42

A mixture of 1-(3-methoxyphenyl)ethylamine (0.32 g),3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.45 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.33 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[1-(3-methoxyphenyl)ethyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide(0.61 g, yield 88%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 89-90° C.

Example 43

A mixture of 2-aminomethyl-5-methylpyrazine (0.25 ml),3-(5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.45 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(5-methyl-2-pyrazinylmethyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide(0.58 g, yield 90%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 124-125° C.

Example 44

A mixture of 4-(1-imidazolyl)aniline (0.51 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.60 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.75 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-(1-imidazolyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.95g, yield 83%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 176-177° C.

Example 45

A mixture of 6-aminoquinoline (0.38 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.56 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(6-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.79 g, yield 89%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:1, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 170-171° C.

Example 46

A mixture of 2-aminopyrazine (0.26 g),3-(5-phenyl-4-isoxazolyl)propionic acid (0.58 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(2-pyrazinyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.46 g, yield58%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 163-164° C.

Example 47

A mixture of 4-(1-morpholino)aniline (0.90 g),3-(5-phenyl-4-isoxazolyl)propionic acid (1.07 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.90 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-(1-morpholino)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (1.23g, yield 66%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from acetone-hexane. melting point: 197-198° C.

Example 48

A mixture of 5-amino-2-(1-morpholino)pyridine (0.85 g),3-(5-phenyl-4-isoxazolyl)propionic acid (1.01 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.85 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.09 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[6-(1-morpholino)-3-pyridyl]-3-(5-phenyl-4-isoxazolyl)propionamide(0.86 g, yield 49%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 146-147° C.

Example 49

A mixture of 4-(1-imidazolyl)aniline (0.85 g),4-(5-phenyl-4-isoxazolyl)butanoic acid (1.21 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.95 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.20 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-(1-imidazolyl)phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (1.68 g,yield 86%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 132-133° C.

Example 50

A mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (18.62 g), conc.sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hr. Thereaction mixture was concentrated, water was added to the residue andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried (MgSO₄) and concentrated. Theresidue was subjected to silica gel column chromatography, and methyl3-(5-phenyl-4-isoxazolyl)propionate (19.03 g, yield 96%) was obtained asa colorless oil from a fraction eluted with ethyl acetate-hexane (1:3,volume ratio). NMR (CDCl₃) δ: 2.59-2.71 (2H, m), 2.95-3.06 (2H, m), 3.68(3H, s), 7.42-7.56 (3H, m), 7.64-7.74 (2H, m), 8.22 (1H, s).

Example 51

To a solution of methyl 3-(5-phenyl-4-isoxazolyl)propionate (18.13 g) intetrahydrofuran (300 ml) was gently added diisobutylaluminum hydride(1.0 M hexane solution, 160 ml) at 0° C., and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-(5-phenyl-4-isoxazolyl)propan-1-ol (15.72 g, yield99%) was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ: 1.82-2.00 (2H, m),2.72-2.88 (2H, m), 3.66-3.78 (2H, m), 7.41-7.56 (3H, m), 7.68-7.78 (2H,m), 8.21 (1H, s).

Example 52

A mixture of 4-(5-phenyl-4-isoxazolyl)butyronitrile (12.83 g) and conc.hydrochloric acid (100 ml) was refluxed overnight. The reaction mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and4-(5-phenyl-4-isoxazolyl)butanoic acid (13.03 g, yield 93%) was obtainedas colorless crystals from a fraction eluted with ethyl acetate-hexane(1:1, volume ratio). The crystals were recrystallized from ethylacetate-hexane. melting point: 67-68° C.

Example 53

A mixture of diethyl 4-aminobenzylphosphonate (1.74 g),4-(5-phenyl-4-isoxazolyl)butanoic acid (1.38 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (1.08 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.38 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-diethylphosphonomethylphenyl)-4-(5-phenyl-4-isoxazolyl)butaneamide(2.56 g, yield 94%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 128-129° C.

Example 54

A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (1.12 g),3-(5-phenyl-4-isoxazolyl)propionic acid (1.04 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.89 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.11 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide(1.58 g, yield 76%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from acetone-hexane. melting point: 167-168° C.

Example 55

A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (0.51 g),4-(5-phenyl-4-isoxazolyl)butanoic acid (0.51 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.40 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide(0.83 g, yield 84%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from acetone-hexane. melting point: 125-126° C.

Example 56

To a mixture of 5-phenylisoxazole-4-carbaldehyde (7.18 g), ethyldiethylphosphonoacetate (9.35 g) and N,N-dimethylformamide (150 ml) wasadded sodium hydride (60%, oil, 1.65 g) at 0° C., and the mixture wasstirred at room temperature for 3 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and ethyl (E)-3-(5-phenyl-4-isoxazolyl)propenoate (8.88g, yield 88%) was obtained as a yellow oil from a fraction eluted withethyl acetate-hexane (1:4, volume ratio). NMR (CDCl₃) δ: 1.33 (3H, t,J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.34 (1H, d, J=15.4 Hz), 7.48-7.82(6H, m), 8.52 (1H, s).

Example 57

A solution of 4-chloromethyl-3-(4-phenylphenyl)isoxazole (3.20 g) intetrahydrofuran (100 ml) was added to a mixture of diethyl malonate(5.70 g), sodium hydride (60%, oil, 1.40 g) and tetrahydrofuran (50 ml)at 0° C. The mixture was stirred at 0° C. for 1 hr and then at roomtemperature overnight. The reaction mixture was acidified with dilutehydrochloric acid and extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried (MgSO₄) and concentrated.The residue was subjected to silica gel column chromatography, and acolorless oil was obtained from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). A mixture of the obtained colorlessoil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxedfor 5 hr. The reaction mixture was concentrated, and water was added tothe residue. The obtained colorless crystals were filtrated to give3-[3-(4-phenylphenyl)-4-isoxazolyl]propionic acid (2.89 g, yield 83%).The crystals were recrystallized from acetone-hexane. melting point:169-170° C.

Example 58

To a solution of methyl 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionate(3.21 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 30 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(4-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.48g, yield 87%) was obtained as a pale yellow oil from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ: 1.38 (1H,br s), 1.82-2.02 (2H, m), 2.70-2.84 (2H, m), 3.64-3.80 (2H, m),7.10-7.26 (2H, m), 7.64-7.80 (2H, m), 8.21 (1H, s).

Example 59

To a solution of diethyl malonate (3.38 g) in tetrahydrofuran (40 ml)was gradually added sodium hydride (60%, oil, 770 mg) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(2,4-difluorophenyl)isoxazole (2.20 g) intetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 15 hr. The reaction mixture wasacidified by pouring into 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was concentrated, and the residue wasdissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid(60 ml) and heated under reflux for 8 hr. The reaction mixture wasconcentrated, and water was added to the residue. The obtained colorlesscrystals were filtrated, dried and recrystallized from ethylacetate-hexane to give a colorless prism (2.10 g, yield 87%) of3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionic acid. melting point:125-126° C.

Example 60

To a solution of 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionicacid (2.20 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml)and the mixture was heated under reflux for 1 hr. The reaction mixturewas concentrated, and iced water was poured into the residue. Theprecipitated crystals (1.70 g, yield 74%) of methyl3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionate were collected byfiltration. The crystals were recrystallized from ethyl acetate-hexaneto give a colorless prism. melting point: 68-69° C.

Example 61

To a solution of 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionic acid(1.25 g) in methanol (40 ml) was added conc. sulfuric acid (1 ml) andthe mixture was heated under reflux for 1 hr. The reaction mixture wasconcentrated, and iced water was poured into the residue. Theprecipitated crystals were collected by filtration. The crystals weresubjected to silica gel column chromatography, and the crystals obtainedfrom a fraction eluted with ethyl acetate-hexane (1:1, volume ratio)were recrystallized from ethyl acetate-hexane to give a colorless prism(1.15 g, yield 87%) of methyl3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionate. melting point: 40-41°C.

Example 62

To a solution of methyl3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionate (1.40 g) intetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 10.3 ml) at 0° C., and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was poured into 2Nhydrochloric acid, concentrated and the precipitated crystals werecollected by filtration and recrystallized from ethyl acetate-hexane togive 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propan-1-ol (970 mg,yield 76%) as a colorless needle. melting point: 85-86° C.

Example 63

To a solution of methyl3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionate (1.05 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 8.7 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propan-1-ol(640 mg, yield 68%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ:1.29 (1H, br s), 1.75-1.95 (2H, m), 2.55-2.65 (2H, m), 3.6-3.75 (2H, m),6.9-7.1 (2H, m), 7.5-7.65 (1H, m), 8.25 (1H, s).

Example 64

To a solution of diethyl malonate (10.1 g) in tetrahydrofuran (60 ml)was gradually added sodium hydride (60%, oil, 2.29 g) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.70 g) intetrahydrofuran (60 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 15 hr. The reaction mixture wasacidified by pouring into 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was concentrated and the residue wasdissolved in a mixture of 6N hydrochloric acid (80 ml) and acetic acid(120 ml). The mixture was heated under reflux for 8 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated, dried and recrystallizedfrom ethyl acetate to give a colorless prism (4.95 g, yield 67%) of3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionic acid. melting point:138-139° C.

Example 65

To a solution of 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionic acid(2.20 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml) andthe mixture was heated under reflux for 1 hr. The reaction mixture wasconcentrated, iced water was poured on the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography, and crystals (3.80 g, yield 86%) ofmethyl 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionate were obtainedfrom a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).The crystals were recrystallized from diethyl ether-isopropyl ether togive a colorless prism. melting point: 34-35° C.

Example 66

To a solution of methyl3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionate (3.10 g) intetrahydrofuran (80 ml) was gently added diisobutylaluminum hydride (1.5M toluene solution, 17 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propan-1-ol(2.02 g, yield 73%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ:1.41 (1H, br t, J=5 Hz), 1.8-2.0 (2H, m), 2.73 (2H, t, J=8 Hz), 3.73(2H, td, J=6, 5 Hz), 6.98 (1H, d, J=0.4 Hz), 7.29 (1H, d, J=4 Hz), 8.17(1H, s).

Example 67

To a solution of methyl3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionate (2.00 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 15 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol(1.67 g, yield 92%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ:1.20-1.32 (1H, br t), 1.70-1.88 (2H, m), 2.44-2.60 (2H, m), 3.56-3.70(2H, m), 7.35-7.39 (2H, m), 7.53-7.57 (1H, m), 8.27 (1H, s).

Example 68

To a solution of methyl3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (1.63 g) intetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 13 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol(1.53 g, yield 97%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 66-67° C.

Example 69

To a solution of 5-(2,4-dichlorophenyl)-4-isoxazolylmethanol (5.15 g) intoluene (100 ml) was added dropwise thionyl chloride (2.00 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (5.89 g), sodium hydride(60%, oil, 1.45 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.85 g, yield72%). The crystals were recrystallized from acetone-hexane. meltingpoint: 106-107° C.

Example 70

To a solution of 5-(3,4-dichlorophenyl)-4-isoxazolylmethanol (6.50 g) intoluene (100 ml) was added dropwise thionyl chloride (3.0 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (8.53 g), sodium hydride(60%, oil, 2.01 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid (5.96 g, yield78%). The crystals were recrystallized from acetone-hexane. meltingpoint: 171-172° C.

Example 71

A mixture of 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (3.68 g),conc. sulfuric acid (0.05 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[5-(4-fluorophenyl)-4-isoxazolyl]propionate(3.50 g, yield 90%) was obtained as a pale yellow oil from a fractioneluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl₃) δ:2.65 (2H, t, J=7.4 Hz), 2.98 (2H, t, J=7.4 Hz), 3.69 (3H, s), 7.12-7.28(2H, m), 7.64-7.78 (2H, m), 8.22 (1H, s).

Example 72

A mixture of 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.00g), conc. sulfuric acid (0.1 ml) and methanol (50 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionate (2.96 g, yield 94%)was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:4, volume ratio). NMR (CDCl₃) δ: 2.46-2.58 (2H, m),2.71-2.81 (2H, m), 3.66 (3H, s), 7.35-7.42 (2H, m), 7.54-7.58 (1H, m),8.28 (1H, s).

Example 73

A mixture of 3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.20g), conc. sulfuric acid (0.1 ml) and methanol (50 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (3.26 g, yield 97%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:4, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 74-75° C.

Example 74

To a solution of 5-(3,5-dichlorophenyl)-4-isoxazolylmethanol (6.06 g) intoluene (100 ml) was added dropwise thionyl chloride (2.7 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (7.96 g), sodium hydride(60%, oil, 1.95 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionic acid (5.96 g, yield84%). The crystals were recrystallized from acetone-hexane. meltingpoint: 143-144° C.

Example 75

A mixture of 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionic acid (3.50g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for4 hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionate (3.49-g, yield 99%)was obtained as a pale yellow oil from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). NMR (CDCl₃) δ: 2.62-2.72 (2H, m),2.92-3.02 (2H, m), 3.70 (3H, s), 7.45 (1H, t, J=1.8 Hz), 7.60 (1H, d,J=1.8 Hz), 8.24 (1H, s).

Example 76

To a solution of methyl3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionate (2.25 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 20 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propan-1-ol(1.65 g, yield 81%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ:1.83-2.00 (2H, m), 2.72-2.86 (2H, m), 3.68-3.80 (2H, m), 7.43 (1H, t,J=1.8 Hz), 7.64 (2H, d, J=1.8 Hz), 8.24 (1H, s).

Example 77

To a solution of 5-(3,4-difluorophenyl)-4-isoxazolylmethanol (4.80 g) intoluene (100 ml) was added dropwise thionyl chloride (2.5 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (7.26 g), sodium hydride(60%, oil, 1.79 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionic acid (4.98 g, yield87%). The crystals were recrystallized from ethyl acetate-hexane.melting point: 102-103° C.

Example 78

A mixture of 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionic acid (3.45g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for4 hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionate (3.56 g, yield 98%)was obtained as a pale yellow oil from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). NMR (CDCl₃) δ: 2.60-2.71 (2H, m),2.92-3.03 (2H, m), 3.69 (3H, s), 7.22-7.65 (3H, m), 8.23 (1H, s).

Example 79

To a solution of methyl3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionate (2.20 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 20 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propan-1-ol(1.88 g, yield 95%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ:1.38 (1H, br s), 1.82-2.00 (2H, m), 2.72-2.84 (2H, m), 3.66-3.82 (2H,m), 7.21-7.38 (1H, m), 7.44-7.66 (2H, m), 8.22 (1H, s).

Example 80

To a solution of 5-(4-nitrophenyl)-4-isoxazolylmethanol (6.56 g) intoluene (100 ml) was added dropwise thionyl chloride (3.3 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (9.56 g), sodium hydride(60%, oil, 2.35 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(4-nitrophenyl)-4-isoxazolyl]propionic acid (6.19 g, yield 79%).The crystals were recrystallized from acetone-hexane. melting point:204-205° C.

Example 81

A mixture of 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionic acid (5.28 g),conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionate(5.45 g, yield 98%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 118-119° C.

Example 82

To a solution of methyl 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionate(1.60 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(4-nitrophenyl)-4-isoxazolyl]propan-1-ol (1.36g, yield 95%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 132-133° C.

Example 83

To a solution of 5-(4-bromophenyl)-4-isoxazolylmethanol (7.55 g) intoluene (50 ml) was added dropwise thionyl chloride (3.3 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (9.58 g), sodium hydride(60%, oil, 2.36 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(4-bromophenyl)-4-isoxazolyl]propionic acid (6.18 g, yield 70%).The crystals were recrystallized from ethyl acetate-hexane. meltingpoint: 164-165° C.

Example 84

A mixture of 3-[5-(4-bromophenyl)-4-isoxazolyl]propionic acid (5.00 g),conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[5-(4-bromophenyl)-4-isoxazolyl]propionate(5.03 g, yield 96%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 58-59° C.

Example 85

To a solution of methyl 3-[5-(4-bromophenyl)-4-isoxazolyl]propionate(4.06 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 30 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(4-bromophenyl)-4-isoxazolyl]propan-1-ol (3.58g, yield 97%) was obtained as colorless crystals from a fraction elutedwith ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 72-73° C.

Example 86

To a solution of 5-(3-chlorophenyl)-4-isoxazolylmethanol (6.80 g) intoluene (100 ml) was added dropwise thionyl chloride (3.6 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml),and added to a mixture of diethyl malonate (10.38 g), sodium hydride(60%, oil, 2.56 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(3-chlorophenyl)-4-isoxazolyl]propionic acid (5.95 g, yield 73%).The crystals were recrystallized from acetone-hexane. melting point:110-111° C.

Example 87

A mixture of 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionic acid (3.10 g),conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionate(3.06 g, yield 93%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl₃) δ:2.59-2.71 (2H, m), 2.93-3.05 (2H, m), 3.69 (3H, s), 7.36-7.50 (2H, m),7.54-7.65 (1H, m), 7.69-7.73 (1H, m), 8.23 (1H, s).

Example 88

To a solution of methyl 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionate(2.50 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 25 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(3-chlorophenyl)-4-isoxazolyl]propan-1-ol (2.38g, yield 95%) was obtained as a colorless oil from a fraction elutedwith ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ: 1.39 (1H,br s), 1.84-2.00 (2H, m), 2.72-2.86 (2H, m), 3.66-3.80 (2H, m),7.38-7.49 (2H, m), 7.56-7.68 (1H, m), 7.70-7.77 (1H, m), 8.23 (1H, s).

Example 89

To a solution of 5-(1,3-benzodioxol-5-yl)-4-isoxazolylmethanol (7.90 g)in toluene (150 ml) was added dropwise thionyl chloride (4.0 ml) at 0°C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (200 ml) and added to a mixture of diethylmalonate (11.55 g), sodium hydride (60%, oil, 2.85 g) andtetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1hr and then at room temperature overnight. The reaction mixture wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionic acid (7.36 g,yield 78%). The crystals were recrystallized from acetone-hexane.melting point: 150-151° C.

Example 90

A mixture of 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionic acid(4.19 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionate (4.26 g, yield 97%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 84-85° C.

Example 91

To a solution of methyl3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propionate (2.70 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 25 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(1,3-benzodioxol-5-yl)-4-isoxazolyl]propan-1-ol(2.33 g, yield 96%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 45-46° C.

Example 92

To a solution of 5-(3-chloro-4-fluorophenyl)-4-isoxazolylmethanol (7.01g) in toluene (100 ml) was added dropwise thionyl chloride (3.5 ml) at0° C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml) and added to a mixture of diethylmalonate (9.89 g), sodium hydride (60%, oil, 2.43 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (6.68 g,yield 80%). The crystals were recrystallized from acetone-hexane.melting point: 118-119° C.

Example 93

A mixture of 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid(3.10 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (3.18 g, yield97%) was obtained as a pale yellow oil from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). NMR (CDCl₃) δ: 2.60-2.72 (2H, m),2.91-3.03 (2H, m), 3.69 (3H, s), 7.22-7.33 (1H, m), 7.52-7.66 (1H, m),7.74-7.82 (1H, m), 8.23 (1H, s).

Example 94

To a solution of methyl3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (3.00 g) intetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 25 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.59 g, yield95%) was obtained as a pale yellow oil from a fraction eluted with ethylacetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ: 1.40 (1H, br s),1.82-2.00 (2H, m), 2.70-2.84 (2H, m), 3.66-3.78 (2H, m), 7.20-7.32 (1H,m), 7.55-7.67 (1H, m), 7.76-7.84 (1H, m), 8.22 (1H, s).

Example 95

To a solution of diethyl malonate (5.82 g) in tetrahydrofuran (40 ml)was gradually added sodium hydride (60%, oil, 1.32 g) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(4-chloro-3-methylphenyl)isoxazole (4.00 g) intetrahydrofuran (40 ml) was added dropwise at 0° C. and the mixture wasstirred at room temperature for 15 hr. The reaction mixture was pouredinto water, acidified with 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in a mixture of 6Nhydrochloric acid (40 ml) and acetic acid (60 ml) and heated underreflux for 8 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated,dried and recrystallized from ethyl acetate to give a colorless prism(2.56 g, yield 58%) of3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionic acid. meltingpoint: 158-159° C.

Example 96

To a solution of 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionicacid (1.80 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml)and the mixture was heated under reflux for 1 hr. The reaction mixturewas concentrated, and iced water was poured on the residue. Theprecipitated crystals of methyl3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionate were filtratedand recrystallized from ethyl acetate-hexane to give a colorless needle(1.72 g, yield 91%). melting point: 60-61° C.

Example 97

To a solution of methyl3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionate (1.20 g) intetrahydrofuran (40 ml) was gently added diisobutylaluminum hydride (1.0M toluene solution, 9.5 ml) at 0° C., and the mixture was stirred atroom temperature for 3 hr. Water was carefully added to the reactionmixture, acidified with dilute hydrochloric acid and extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated. The residue was subjected to silica gelcolumn chromatography and the crystals obtained from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio) were recrystallized fromethyl acetate-hexane to give a colorless needle of3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propan-1-ol (780 mg, yield72%). melting point: 50-51° C.

Example 98

To a solution of diethyl malonate (2.89 g) in tetrahydrofuran (40 ml)was gradually added sodium hydride (60%, oil, 655 mg) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(2,5-dichlorophenyl)isoxazole (2.15 g) intetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 15 hr. The reaction mixture was pouredinto water, acidified with 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in a mixture of 6Nhydrochloric acid (40 ml) and acetic acid (60 ml) and heated underreflux for 8 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrateddried and recrystallized from ethyl acetate to give a colorless prism(1.35 g, yield 58%) of 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionicacid. melting point: 103-104° C.

Example 99

To a solution of 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionic acid(800 mg) in methanol (30 ml) was added conc. sulfuric acid (1 ml) andthe mixture was heated under reflux for 1 hr. The reaction mixture wasconcentrated, iced water was poured on the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and methyl3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionate was obtained as acolorless oil (500 mg, yield 60%) from a fraction eluted with ethylacetate-hexane (1:9, volume ratio).

NMR (CDCl₃) δ: 2.5-2.85 (4H, m), 3.66 (3H, s), 7.35-7.5 (3H, m), 8.28(1H, s).

Example 100

To a solution of 5-(3,4-dimethoxyphenyl)-4-isoxazolylmethanol (6.65 g)in toluene (100 ml) was added dropwise thionyl chloride (3.1 ml) at 0°C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml) and added to a mixture of diethylmalonate (9.10 g), sodium hydride (60%, oil, 2.25 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionic acid (7.36 g,yield 78%). The crystals were recrystallized from acetone-hexane.melting point: 169-170° C.

Example 101

A mixture of 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionic acid(2.53 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionate (2.58 g, yield 97%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 68-69° C.

Example 102

To a solution of methyl3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionate (1.70 g) intetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 15 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propan-1-ol(1.26 g, yield 82%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 55-56° C.

Example 103

To a solution of diethyl malonate (10.3 g) in tetrahydrofuran (80 ml)was gradually added sodium hydride (60%, oil, 2.34 g) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.00 g) intetrahydrofuran (70 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 8 hr. The reaction mixture was pouredinto water, acidified with 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in a mixture of 6Nhydrochloric acid (50 ml) and acetic acid (100 ml), and heated underreflux for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue to give colorless crystals (4.68 g, yield 61%) of3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionic acid. The crystals wererecrystallized from ethyl acetate-isopropyl ether to give a colorlessprism. melting point: 124-125° C.

Example 104

To a solution of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionic acid(3.70 g) in methanol (100 ml) was added conc. sulfuric acid (1 ml) andthe mixture was heated under reflux for 1 hr. The reaction mixture wasconcentrated, iced water was poured on the residue and the precipitatedcrystals of methyl 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionatewere filtrated, which were recrystallized from ethyl acetate-isopropylether to give a colorless prism (3.60 g, yield 92%). melting point:57-58° C.

Example 105

To a solution of methyl3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionate (1.60 g) intetrahydrofuran (60 ml) was gently added diisobutylaluminum hydride(0.95 M toluene solution, 15.2 ml) at 0° C., and the mixture was stirredat room temperature for 1 hr. The reaction mixture was poured intodilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and the crystals obtained from a fraction eluted withacetone-hexane (1:1, volume ratio) were recrystallized from ethylacetate-hexane to give3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol as a colorless prismcrystal (1.36 g, yield 95%). melting point: 54-55° C.

Example 106

To a solution of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol (500mg) in tetrahydrofuran (30 ml) was gradually added m-chloroperbenzoicacid (870 mg) at 0° C., and the mixture was stirred at room temperaturefor 1 hr. The reaction mixture was poured into iced water, and extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel column chromatography to give crystals (480 mg, yield 85%) of3-[5-(4-methylsulfonylphenyl)-4-isoxazolyl]propan-1-ol from a fractioneluted with acetone-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-isopropyl ether to give a colorlessneedle. melting point: 125-126° C.

Example 107

To a solution of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol (900mg) in acetonitrile (20 ml) was gradually added m-chloroperbenzoic acid(750 mg) at 0° C., and the mixture was stirred at room temperature for 1hr. The reaction mixture was poured into iced water and extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated. The residue was subjected to silica gelcolumn chromatography, and crystals (390 mg, yield 41%) of3-[5-(4-methylsulfinylphenyl)-4-isoxazolyl]propan-1-ol were obtainedfrom a fraction eluted with acetone-hexane (2:1, volume ratio). Thecrystals were recrystallized from ethyl acetate-diethyl ether to give acolorless prism. melting point: 73-74° C.

Example 108

To a solution of 5-(4-chloro-3-fluorophenyl)-4-isoxazolylmethanol (7.80g) in toluene (150 ml) was added dropwise thionyl chloride (4.0 ml) at0° C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was 0.194 concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (150 ml) and added to a mixture of diethylmalonate (10.98 g), sodium hydride (60%, oil, 2.71 g) andtetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1hr and then at room temperature overnight. The reaction mixture wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid (7.20 g,yield 78%). The crystals were recrystallized from acetone-hexane.melting point: 139-140° C.

Example 109

A mixture of 3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid(5.08 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (5.25 g, yield98%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 53-54° C.

Example 110

To a solution of methyl3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (3.30 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 25 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.79 g, yield94%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 51-52° C.

Example 111

To a solution of 3-(3,4-dichlorophenyl)-4-isoxazolylmethanol (5.50 g) intoluene (50 ml) was added dropwise thionyl chloride (2.5 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml)and added to a mixture of diethyl malonate (7.21 g), sodium hydride(60%, oil, 1.79 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid (5.09 g, yield79%). The crystals were recrystallized from acetone-hexane. meltingpoint: 181-182° C.

Example 112

A mixture of 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.03g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for4 hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (3.15 g, yield 99%)was obtained as colorless crystals from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). The crystals were recrystallizedfrom ethyl acetate-hexane. melting point: 87-88° C.

Example 113

To a solution of methyl3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propionate (2.40 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 20 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[3-(3,4-dichlorophenyl)-4-isoxazolyl]propan-1-ol(2.06 g, yield 95%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 62-63° C.

Example 114

To a solution of 3-(3-chloro-4-fluorophenyl)-4-isoxazolylmethanol (6.60g) in toluene (75 ml) was added dropwise thionyl chloride (3.5 ml) at 0°C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml), and added to a mixture of diethylmalonate (9.31 g), sodium hydride (60%, oil, 2.30 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (5.71 g,yield 73%). The crystals were recrystallized from acetone-hexane.melting point: 140-141° C.

Example 115

A mixture of 3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid(4.34 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (4.39 g, yield96%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 39-40° C.

Example 116

To a solution of methyl3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (3.50 g) intetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 30 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[3-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (2.89 g, yield92%) was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ: 1.30 (1H, t, J=5.2Hz), 1.74-1.94 (2H, m), 2.62-2.74 (2H, m), 3.64-3.76 (2H, m), 7.18-7.31(1H, m), 7.50-7.60 (1H, m), 7.74 (1H, dd, J=2.2, 7.0 Hz), 8.29 (1H, s).

Example 117

To a solution of 3-(4-chloro-3-fluorophenyl)-4-isoxazolylmethanol (9.04g) in toluene (100 ml) was added dropwise thionyl chloride (4.5 ml) at0° C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml), and added to a mixture of diethylmalonate (12.75 g), sodium hydride (60%, oil, 3.15 g) andtetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1hr and then at room temperature overnight. The reaction mixture wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid (7.72 g,yield 72%). The crystals were recrystallized from acetone-hexane.melting-point: 148-149° C.

Example 118

A mixture of 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionic acid(5.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (5.01 g, yield96%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 57-58° C.

Example 119

To a solution of methyl3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (3.69 g) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 30 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propan-1-ol (3.06 g, yield92%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 54-55° C.

Example 120

A mixture of 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionic acid (2.75g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for4 hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionate (2.76 g, yield 95%) wasobtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). NMR (CDCl₃) δ: 2.58-2.70 (2H, m),2.92-3.04 (2H, m), 3.68 (3H, s), 3.87 (3H, s), 6.96-7.06 (2H, m),7.59-7.69 (2H, m), 8.18 (1H, s).

Example 121

To a solution of methyl 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionate(2.50 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propan-1-ol(2.03 g, yield 91%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl₃) δ:1.82-1.98 (2H, m), 2.70-2.82 (2H, m), 3.66-3.78 (2H, m), 3.86 (3H, s),6.95-7.06 (2H, m), 7.62-7.73 (2H, m), 8.18 (1H, s).

Example 122

A mixture of 3-[5-(4-methylphenyl)-4-isoxazolyl]propionic acid (4.00 g),conc. sulfuric acid (2 ml) and methanol (80 ml) was refluxed for 1 hr.The reaction mixture was concentrated, water was added to the residueand the mixture was extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried (MgSO₄) and concentrated.The residue was subjected to silica gel column chromatography, andmethyl 3-[5-(4-methylphenyl)-4-isoxazolyl]propionate (3.35 g, yield 79%)was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:7, volume ratio). NMR (CDCl₃) δ: 2.41 (3H, s), 2.63(2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 3.68 (3H, s), 7.30 (2H, d,J=8 Hz), 7.59 (2H, d, J=8 Hz), 8.20 (1H, s).

Example 123

To a solution of diethyl malonate (3.55 g) in tetrahydrofuran (50 ml)was gradually added sodium hydride (60%, oil, 710 mg) at 0° C. Themixture was stirred for 10 min and a solution of4-chloromethyl-5-(4,5-dichloro-2-thienyl)isoxazole (2.38 g) intetrahydrofuran (50 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 15 hr. The reaction mixture was pouredinto water, acidified with 2N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was dissolved in a mixture of 6Nhydrochloric acid (60 ml) and acetic acid (90 ml), and the solution washeated under reflux for 8 hr. The reaction mixture was concentrated, andwater was added to the residue to give colorless crystals (2.04 g, yield79%) of 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionic acid. Thecrystals were recrystallized from ethyl acetate-hexane to give acolorless prism. melting point: 142-143° C.

Example 124

To a solution of 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionicacid (1.60 g) in methanol (30 ml) was added conc. sulfuric acid (1 ml)and the mixture was heated under reflux for 1 hr. The reaction mixturewas concentrated, iced water was poured on the residue and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and crystals (1.34 g,yield 80%) of methyl3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionate was obtained froma fraction eluted with ethyl acetate-hexane (1:7, volume ratio). Thecrystals were recrystallized from diethyl ether-hexane to give acolorless needle. melting point: 49-50° C.

Example 125

To a solution of 3-(3-bromo-4-fluorophenyl)-4-isoxazolylmethanol (6.79g) in toluene (50 ml) was added dropwise thionyl chloride (3.0 ml) at 0°C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml) and added to a mixture of diethylmalonate (8.11 g), sodium hydride (60%, oil, 2.00 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid (6.33 g,yield 81%). The crystals were recrystallized from acetone-hexane.melting point: 151-152° C.

Example 126

A mixture of 3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid(3.15 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (3.11 g, yield95%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 57-58° C.

Example 127

To a solution of methyl3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (1.68 g) intetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 15 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[3-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (1.49 g, yield97%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 0.40-41° C.

Example 128

To a solution of 5-(3-bromo-4-fluorophenyl)-4-isoxazolylmethanol (6.49g) in toluene (100 ml) was added dropwise thionyl chloride (2.6 ml) at0° C., and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated, saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (100 ml) and added to a mixture of diethylmalonate (7.65 g), sodium hydride (60%, oil, 1.87 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid (5.06 g,yield 67%). The crystals were recrystallized from acetone-hexane.melting point: 136-137° C.

Example 129

A mixture of 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionic acid(2.38 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (2.39 g, yield96%) was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). NMR (CDCl₃) δ: 2.60-2.71 (2H, m),2.91-3.03 (2H, m), 3.69 (3H, s), 7.18-7.32 (1H, m), 7.60-7.70 (1H, m),7.94 (1H, dd, J 2.2, 6.2 Hz), 8.23 (1H, s).

Example 130

To a solution of methyl3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (1.43 g) intetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0M hexane solution, 10 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (1.11 g, yield85%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 57-58° C.

Example 131

To a solution of 5-(4-phenylphenyl)-4-isoxazolylmethanol (7.11 g) intoluene (200 ml) was added dropwise thionyl chloride (3.10 ml) at 0° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was concentrated, saturated aqueous sodium hydrogencarbonate wasadded to the residue, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was dissolved in tetrahydrofuran (100 ml),and added to a mixture of diethyl malonate (9.07 g), sodium hydride(60%, oil, 2.22 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(70 ml) and acetic acid (70 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-(4-phenylphenyl)-4-isoxazolyl]propionic acid (6.30 g, yield 76%).The crystals were recrystallized from ethyl acetate-hexane. meltingpoint: 94-95° C.

Example 132

A mixture of 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionic acid (6.00 g),conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4hr. The reaction mixture was concentrated, water was added to theresidue and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and methyl 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionate(5.91 g, yield 94%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 103-104° C.

Example 133

To a solution of methyl 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionate(1.00 g) in tetrahydrofuran (25 ml) was gently added diisobutylaluminumhydride (1.0 M hexane solution, 8.0 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(4-phenylphenyl)-4-isoxazolyl]propan-1-ol(0.656 g, yield 72%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (2:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 94-95° C.

Example 134

A mixture of 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionic acid(2.74 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) wasrefluxed for 4 hr. The reaction mixture was concentrated, water wasadded to the residue and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, dried (MgSO₄)and concentrated. The residue was subjected to silica gel columnchromatography, and methyl3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionate (2.22 g, yield78%) was obtained as colorless crystals from a fraction eluted withethyl acetate-hexane (1:3, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 54-55° C.

Example 135

A mixture of diethyl 4-aminobenzylphosphonate (0.58 g),3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.50 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, andN-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide(0.87 g, yield 88%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 114-115° C.

Example 136

To a mixture of 3-methyl-5-phenylisoxazole-4-carbaldehyde (4.94 g),ethyl diethylphosphonoacetate (6.53 g) and N,N-dimethylformamide (70 ml)was added sodium hydride (60%, oil, 1.13 g) at 0° C., and the mixturewas stirred at room temperature for 3 hr. The reaction mixture waspoured into dilute hydrochloric acid, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried (MgSO₄) and concentrated. The residue was subjected to silica gelcolumn chromatography, and a yellow oil was obtained from a fractioneluted with ethyl acetate-hexane (1:4, volume ratio). A mixture of theobtained yellow oil, 2N hydrochloric acid (50 ml) and acetic acid (50ml) was refluxed for 3 hr. The reaction mixture was concentrated, andwater was added to the residue. The obtained colorless crystals werefiltrated to give (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid(4.02 g, yield 93%). The crystals were recrystallized from ethylacetate-hexane. melting point: 173-174° C.

Example 137

A mixture of methyl 4-aminobenzoate (0.30 g),(E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.35 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.27 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and(E)-N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide(0.51 g, yield 92%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 174-175° C.

Example 138

A mixture of ethyl 4-aminophenylacetate (1.11 g),(E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.95 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.75 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) andN,N-dimethylformamide (20 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and(E)-N-(4-ethoxycarbonylmethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide(1.82 g, yield 97%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 164-165° C.

Example 139

A mixture of diethyl 4-aminobenzylphosphonate (0.43 g),(E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.50 g),1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.38 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) andN,N-dimethylformamide (15 ml) was stirred at room temperature overnight.The reaction mixture was poured into water and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with dilutehydrochloric acid, saturated aqueous sodium hydrogencarbonate and thensaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and(E)-N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide(0.71 g, yield 83%) was obtained as colorless crystals from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). The crystals wererecrystallized from ethyl acetate-hexane. melting point: 155-156° C.

Example 140

A solution of 4-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole (2.90g) in tetrahydrofuran (100 ml) was added to a mixture of diethylmalonate (5.35 g), sodium hydride (60%, oil, 1.30 g) and tetrahydrofuran(50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[3-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (2.49 g,yield 79%). The crystals were recrystallized from ethyl acetate-hexane.melting point: 173-174° C.

Example 141

4-Chloromethyl-3-(4-chlorophenyl)-5-methylisoxazole (1.21 g) wasdissolved in tetrahydrofuran (50 ml) and added to a mixture of diethylmalonate (1.20 g), sodium hydride (60%, oil, 0.21 g) and tetrahydrofuran(20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio).

A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml)and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture wasconcentrated, and water was added to the residue. The obtained colorlesscrystals were filtrated to give3-[3-(4-chlorophenyl)-5-methyl-4-isoxazolyl]propionic acid (1.20 g,yield 90%). The crystals were recrystallized from ethanol. meltingpoint: 187-188° C.

Example 142

To a solution of methyl propionylacetate (9.95 g) and4-chloro-N-hydroxybenzenecarboxyimidoyl chloride (9.65 g) intetrahydrofuran (100 ml) was gently added a solution of triethylamine(15 ml) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred atroom temperature overnight, the reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio).

To a solution of the obtained colorless oil in tetrahydrofuran (100 ml)was gently added diisobutylaluminum hydride (1.0 M hexane solution, 110ml) at 0° C. and the mixture was stirred at room temperature for 30 min.The reaction mixture was poured into dilute hydrochloric acid, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated to give acolorless oil. A mixture of the obtained colorless oil and thionylchloride (10.0 ml) was stirred at 0° C. for 30 min. The reaction mixturewas concentrated, saturated aqueous sodium hydrogencarbonate was addedto the residue, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated to give a colorless oil. The obtained colorless oil wasdissolved in tetrahydrofuran (100 ml) and added to a mixture of diethylmalonate (2.40 g), sodium hydride (60%, oil, 0.42 g) and tetrahydrofuran(20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then atroom temperature overnight. The reaction mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtainedcolorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) wasrefluxed for 5 hr. The reaction mixture was concentrated, and water wasadded to the residue. The obtained colorless crystals were filtrated togive 3-[3-(4-chlorophenyl)-5-ethyl-4-isoxazolyl]propionic acid (4.33 g,yield 30%). The crystals were recrystallized from ethanol. meltingpoint: 164-165° C.

Example 143

To a solution of ethyl benzoylacetate (5.76 g) and sodium hydride (60%,oil, 0.12 g) in tetrahydrofuran (60 ml) was gently added methyl acrylate(3.2 ml) at room temperature and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio).

A mixture of the obtained colorless oil, hydroxylamine hydrochloride(1.68 g) and isopropyl alcohol (65 ml) was refluxed for 16 hr. Thereaction mixture was poured into dilute hydrochloric acid, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated to give acolorless oil. A mixture of the obtained colorless oil, 2N sodiumhydroxide (20 ml) and methanol (30 ml) was stirred at room temperaturefor 1 hr. The reaction mixture was acidified with dilute hydrochloricacid and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated. Theobtained colorless crystals were filtrated to give3-[5-hydroxy-3-phenyl-4-isoxazolyl]propionic acid (2.49 g, yield 36%).The crystals were recrystallized from ethanol. melting point: 183-184°C.

Example 144

A solution of4-chloromethyl-5-methyl-3-(4-trifluoromethylphenyl)isoxazole (1.37 g) intetrahydrofuran (50 ml) was added to a mixture of diethyl malonate (1.20g), sodium hydride (60%, oil, 0.21 g) and tetrahydrofuran (20 ml) at 0°C. The mixture was stirred at 0° C. for 1 hr and then at roomtemperature overnight. The reaction mixture was acidified with dilutehydrochloric acid and extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried (MgSO₄) and concentrated.The residue was subjected to silica gel column chromatography, and acolorless oil was obtained from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). A mixture of the obtained colorlessoil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxedfor 5 hr. The reaction mixture was concentrated, and water was added tothe residue. The obtained colorless crystals were filtrated to give3-[5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid(1.25 g, yield 84%). The crystals were recrystallized fromethanol-hexane. melting point: 138-139° C.

Example 145

To a solution of methyl acetoacetate (8.88 g) and3-trifluoromethyl-N-hydroxybenzenecarboxyimidoyl chloride (11.35 g) intetrahydrofuran (100 ml) was gently added triethylamine (15 ml) intetrahydrofuran (10 ml) at 0° C. and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio). To a solution of theobtained colorless oil in tetrahydrofuran (100 ml) was gently addeddiisobutylaluminum hydride (1.0 M hexane solution, 110 ml) at 0° C. andthe mixture was stirred at room temperature for 30 min. The reactionmixture was poured into dilute hydrochloric acid, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated to give a colorless oil.

A mixture of the obtained colorless oil and thionyl chloride (5.0 ml)was stirred at 0° C. for 30 min. The reaction mixture was concentrated,saturated aqueous sodium hydrogencarbonate was added to the residue, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated brine, dried (MgSO₄) and concentrated. Asolution of the obtained colorless oil in tetrahydrofuran (100 ml) andadded to a mixture of diethyl malonate (12.20 g), sodium hydride (60%,oil, 3.05 g) and tetrahydrofuran (50 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hr and then at room temperature overnight. Thereaction mixture was acidified with dilute hydrochloric acid andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel column chromatography, and a colorless oil wasobtained from a fraction eluted with ethyl acetate-hexane (1:3, volumeratio). A mixture of the obtained colorless oil, 6N hydrochloric acid(50 ml) and acetic acid (50 ml) was refluxed for 5 hr. The reactionmixture was concentrated, and water was added to the residue. Theobtained colorless crystals were filtrated to give3-[5-methyl-3-(3-trifluoromethylphenyl)-4-isoxazolyl]propionic acid(6.54 g, yield 43%). The crystals were recrystallized fromethanol-water. melting point: 63-64° C.

Example 146

A mixture of dibenzoylmethane (4.48 g), methyl acrylate (1.8 ml),potassium t-butoxide (0.23 g) and N,N-dimethylformamide (40 ml) wasstirred at room temperature overnight. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio). A mixture of the obtainedcolorless oil, hydroxylamine hydrochloride (1.00 g) and isopropylalcohol (50 ml) was refluxed for 6 hr. The reaction mixture was pouredinto dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated to give a colorless oil. A mixture of theobtained colorless oil, 2N sodium hydroxide (20 ml) and methanol (30 ml)was stirred at room temperature for 2 hr. The reaction mixture wasacidified with dilute hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, dried(MgSO₄) and concentrated. The obtained colorless crystals were filtratedto give 3-[3,5-diphenyl-4-isoxazolyl]propionic acid (1.91 g, yield 33%).The crystals were recrystallized from ethanol. melting point: 152-153°C.

Example 147

To a solution of methyl acetoacetate (8.88 g) and2-chloro-N-hydroxybenzenecarboxyimidoyl chloride (9.65 g) intetrahydrofuran (100 ml) was gently added a solution of triethylamine(15 ml) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred atroom temperature overnight, the reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and a colorless oil was obtained from a fraction elutedwith ethyl acetate-hexane (1:9, volume ratio).

To a solution of the obtained colorless oil in tetrahydrofuran (100 ml)was gently added diisobutylaluminum hydride (1.0 M hexane solution, 110ml) at 0° C. and the mixture was stirred at room temperature for 30 min.The reaction mixture was poured into dilute hydrochloric acid, and themixture was extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine, dried (MgSO₄) and concentrated to give acolorless oil. A mixture of the obtained colorless oil and thionylchloride (5.0 ml) was stirred at 0° C. for 30 min. The reaction mixturewas concentrated, saturated aqueous sodium hydrogencarbonate was addedto the residue, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. A solution of the obtained colorless oil intetrahydrofuran (100 ml) was added to a mixture of diethyl malonate(12.20 g), sodium hydride (60%, oil, 3.05 g) and tetrahydrofuran (50 ml)at 0° C. The mixture was stirred at 0° C. for 1 hr and then at roomtemperature overnight. The reaction mixture was acidified with dilutehydrochloric acid and extracted with ethyl acetate. The ethyl acetatelayer was washed with saturated brine, dried (MgSO₄) and concentrated.The residue was subjected to silica gel column chromatography, and acolorless oil was obtained from a fraction eluted with ethylacetate-hexane (1:3, volume ratio). A mixture of the obtained colorlessoil, 6N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxedfor 5 hr. The reaction mixture was concentrated, and water was added tothe residue. The obtained colorless crystals were filtrated to give3-[3-(2-chlorophenyl)-5-methyl-4-isoxazolyl]propionic acid (5.40 g,yield 40%). The crystals were recrystallized from ethyl acetate-hexane.melting point: 79-81° C.

Example 148

To a solution of methyl 3-[5-(4-methylphenyl)-4-isoxazolyl]propionate(2.00 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminumhydride (0.95 M hexane solution, 21.5 ml) at 0° C., and the mixture wasstirred at room temperature for 1 hr. Sodium sulfate 10 hydrate (6.57 g)was added to the reaction mixture and the mixture was stirred for 2 hr,after which an insoluble material was filtered off. The filtrate wasconcentrated and the residue was subjected to silica gel columnchromatography, and 3-[5-(4-methylphenyl)-4-isoxazolyl]propan-1-ol (1.53g, yield 86%) was obtained as a colorless oil from a fraction elutedwith ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ: 1.25-1.35(1H, m), 1.8-2.0 (2H, m), 2.41 (3H, s), 2.7-2.85 (2H, m), 3.65-3.8 (2H,m), 7.29 (2H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 8.19 (1H, s).

Example 149

To a solution of methyl3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionate (1.30 g) intetrahydrofuran (40 ml) was gently added diisobutylaluminum hydride(0.95 M hexane solution, 11.2 ml) at room temperature, and the mixturewas stirred for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propan-1-ol (1.05 g, yield89%) was obtained as a colorless oil from a fraction eluted with ethylacetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ: 1.35-1.5 (1H, m),1.8-2.0 (2H, m), 2.65-2.8 (2H, m), 3.65-4.0 (2H, m), 7.29 (1H, s), 8.19(1H, s).

Example 150

To a solution of methyl3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionate (500 mg) intetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0M toluene solution, 4.2 ml) and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was poured into dilutehydrochloric acid, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated brine, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel columnchromatography, and 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propan-1-ol(420 mg, yield 93%) was obtained as a colorless oil from a fractioneluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl₃) δ:1.28 (1H, t, J=5 Hz), 1.7-1.9 (2H, m), 2.5-2.6 (2H, m), 3.65 (2H, td,J=6, 5 Hz), 7.35-7.5 (3H, m), 8.27 (1H, s).

Example 151

A mixture of diethyl 4-aminobenzylphosphonate (0.73 g),3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (0.49 g),1-hydroxy-7-aza-1H-1,2,3-benzotriazole (HOAT) (0.40 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) (0.45 g) andN,N-dimethylformamide (5 ml) was stirred at room temperature overnight.The reaction mixture was poured into a 1N aqueous hydrochloric acidsolution and extracted with ethyl acetate. The ethyl acetate layer waswashed with 10% aqueous potassium carbonate solution, and then withsaturated brine, dried (MgSO₄) and concentrated. The obtained solid wasrecrystallized from ethyl acetate-hexane to giveN-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide(0.67 g, yield 70%) as a colorless prism. melting point: 134-135° C.

Elemental analysis:

Calculated (C₂₃H₂₆FN₂O₅P) C, 60.00; H, 5.69; N, 6.08. Found C, 59.83; H,5.52; N, 6.03.

HPLC analysis: purity 100% (retention time: 3.735 min)

MS (ESI+): 461 (M+H)

NMR (CDCl₃) δ: 1.23 (6H, t, J=7 Hz), 2.69 (2H, t, J=7 Hz), 3.0-3.2 (4H,m), 3.9-4.1 (4H, m), 7.1-7.3 (4H, m), 7.38 (2H, d, J=8.5 Hz), 7.7-7.8(2H, m), 8.13 (1H, br s), 8.26 (1H, s).

Example 152

A mixture of diethyl 4-aminobenzylphosphonate (72.9 mg),3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (57 mg),1-hydroxy-7-aza-1H-1,2,3-benzotriazole (40 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (45 mg) andN,N-dimethylformamide (0.3 ml) was stirred at room temperatureovernight. The reaction mixture was directly introduced into preparativeHPLC and purified to giveN-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionamide.

yield: 40 mg (yield 71%)

HPLC analysis: purity 100% (retention time: 3.858 min)

MS (ESI+): 511 (M+H)

In the same manner as in Example 152, the following compounds weresynthesized.

Example 153N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionamide

yield: 80 mg (yield: 82%)

HPLC analysis: purity 100% (retention time: 3.713 min)

MS (ESI+): 489 (M+H)

NMR (CDCl₃) δ: 1.23 (6H, t, J=7 Hz), 2.53 (3H, s), 2.68 (2H, t, J=7 Hz),3.0-3.1 (4H, m), 3.9-4.05 (4H, m), 7.1-7.2 (2H, m), 7.3-7.4 (4H, m),7.66 (2H, d, J=8.5 Hz), 8.08 (1H, br s), 8.24 (1H, s).

Example 154N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionamide

yield: 35 mg (yield: 74%)

HPLC analysis: purity 100% (retention time: 3.554 min)

MS (ESI+): 479 (M+H)

Example 155N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionamide

yield: 71 mg (yield: 73%)

HPLC analysis: purity 100% (retention time: 3.779 min)

MS (ESI+): 483 (M+H)

Example 156N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionamide

yield: 82 mg (yield: 78%)

HPLC analysis: purity 100% (retention time: 3.914 min)

MS (ESI+): 527 (M+H)

NMR (CDCl₃) δ: 1.23 (6H, t, J=7 Hz), 2.71 (2H, t, J=7 Hz), 3.0-3.1 (4H,m), 3.9-4.05 (4H, m), 7.1-7.2 (2H, m), 7.3-7.4 (4H, m), 7.79 (2H, d,J=8.5 Hz), 8.29 (1H, s).

Example 157N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionamide

yield: 53 mg (yield: 48%)

HPLC analysis: purity 99.6% (retention time: 3.985 min)

MS (ESI+): 555 (M+H), 557

Example 158

A mixture ofN-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionamide(98 mg), m-chloroperbenzoic acid (60 mg) and tetrahydrofuran (5 ml) wasstirred at room temperature for 4 hr. 10% aqueous sodium sulfitesolution was added to the reaction mixture and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with 10% aqueouspotassium carbonate solution, and then with saturated brine, dried(MgSO₄) and concentrated. The residue was purified by preparative HPLCto giveN-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylsulfinylphenyl)-4-isoxazolyl]propionamide.

yield: 16 mg (yield: 16%)

HPLC analysis: purity 95.1% (retention time: 2.903 min)

MS (ESI+): 505 (M+H)

Example 159

N-[4-(Diethylphosphonomethyl)phenyl]-3-[5-(4-methylsulfonylphenyl)-4-isoxazolyl]propionamidewas obtained from a fraction that later eluted by preparative HPLC inthe experiment of Example 158.

yield: 14 mg (yield: 13%)

HPLC analysis: purity 93.0% (retention time: 3.163 min)

MS (ESI+): 521 (M+H)

Example 160

A mixture of 4-hydroxypiperidine (10 mg),3-[5-(3-chlorophenyl)-4-isoxazolyl]propionic acid (25 mg),PS-carbodiimide (100 mg, manufactured by Argonaut Technologies) anddichloromethane (1 ml) was shaken at room temperature overnight. Thereaction mixture was filtrated and the filtrate was concentrated. Theobtained residue was purified by preparative HPLC to give1-{3-[5-(3-chlorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol.

yield: 15 mg (yield: 46%)

HPLC analysis: purity 98.1% (retention time: 3.084 min)

MS (APCI+): 335 (M+H)

In the same manner as in Example 160, the following compounds weresynthesized.

Example 1613-[5-(3-chlorophenyl)-4-isoxazolyl]-N-methyl-N-(1-methyl-4-piperidinyl)propionamidetrifluoroacetate

yield: 36 mg (yield: 75%)

HPLC analysis: purity 98.9% (retention time: 2.697 min)

MS (APCI+): 362 (M+H)

Example 162N-((3S)-1-{3-[5-(3-chlorophenyl)-4-isoxazolyl]propanoyl}pyrrolidin-3-yl)-2,2,2-trifluoroacetamide

yield: 22 mg (yield: 53%)

HPLC analysis: purity 97.5% (retention time: 3.572 min)

MS (APCI+): 416 (M+H)

Example 163 tert-butyl(3S)-1-{3-[5-(3-chlorophenyl)-4-isoxazolyl]propanoyl}pyrrolidin-3-ylcarbamate

yield: 37 mg (yield: 89%)

HPLC analysis: purity 96.7% (retention time: 3.771 min)

MS (APCI−): 418 (M−H)

Example 1644-{3-[5-(3-chlorophenyl)-4-isoxazolyl]propanoyl}thiomorpholine1,1′-dioxide

yield: 2 mg (yield: 7%)

HPLC analysis: purity 95.8% (retention time: 3.308 min)

MS (APCI+): 369 (M+H)

Example 165

A mixture of diethyl 4-aminobenzylphosphonate (36 mg),3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (27 mg),1-hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30 mg) andN,N-dimethylformamide (0.5 ml) was stirred at room temperatureovernight. The reaction mixture was poured into 1N aqueous hydrochloricacid solution and the mixture was extracted with ethyl acetate. Theethyl acetate layer was concentrated, and the obtained solid waspurified by preparative HPLC to give3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide.

yield: 39 mg (yield: 79%)

HPLC analysis: purity 99.5% (retention time: 3.875 min)

MS (ESI+): 495 (M+H)

In the same manner as in Example 165, the following compounds weresynthesized.

Example 1663-[5-(4-bromophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide

yield: 36 mg (yield: 69%)

HPLC analysis: purity 99.6% (retention time: 3.897 min)

MS (ESI+): 521 (M+H), 523

Example 167N-((3S)-1-{3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propanoyl}pyrrolidin-3-yl)-2,2,2-trifluoroacetamide

yield: 26 mg (yield: 60%)

HPLC analysis: purity 99.8% (retention time: 3.764 min)

MS (ESI+): 434 (M+H)

Example 168N-((3S)-1-{3-[5-(4-bromophenyl)-4-isoxazolyl]propanoyl}pyrrolidin-3-yl)-2,2,2-trifluoroacetamide

yield: 33 mg (yield: 72%)

HPLC analysis: purity 93.6% (retention time: 3.768 min)

MS (ESI+): 460 (M+H), 462

Example 169N-((3S)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}pyrrolidin-3-yl)-2,2,2-trifluoroacetamide

yield: 25 mg (yield: 74%)

HPLC analysis: purity 98.3% (retention time: 3.480 min)

MS (ESI+): 400 (M+H)

Example 1703-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]-N-methyl-N-(1-methyl-4-piperidinyl)propionamidetrifluoroacetate

yield: 36 mg (yield: 69%)

HPLC analysis: purity 99.7% (retention time: 2.910 min)

MS (ESI+): 380 (M+H)

Example 1713-[5-(4-bromophenyl)-4-isoxazolyl]-N-methyl-N-(1-methyl-4-piperidinyl)propionamidetrifluoroacetate

yield: 20 mg (yield: 38%)

HPLC analysis: purity 99.2% (retention time: 2.925 min)

MS (ESI+): 406 (M+H), 408

Example 1723-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methyl-N-(1-methyl-4-piperidinyl)propionamidetrifluoroacetate

yield: 23 mg (yield: 49%)

HPLC analysis: purity 97.5% (retention time: 2.654 min)

MS (ESI+): 346 (M+H)

Example 1731-{3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol

yield: 34 mg (yield: 96%)

HPLC analysis: purity 95.5% (retention time: 3.255 min)

MS (ESI+): 353 (M+H)

Example 1741-{3-[5-(4-bromophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol

yield: 11 mg (yield: 28%)

HPLC analysis: purity 98.5% (retention time: 3.264 min)

MS (ESI+): 379 (M+H), 381

Example 1751-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol

yield: 22 mg (yield: 68%)

HPLC analysis: purity 89.5% (retention time: 2.952 min)

MS (ESI+): 319 (M+H)

Example 1761-{3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-furoyl)piperazine

yield: 32 mg (yield: 75%)

HPLC analysis: purity 95.9% (retention time: 3.634 min)

MS (ESI+): 432 (M+H)

Example 1771-{3-[5-(4-bromophenyl)-4-isoxazolyl]propanoyl}-4-(2-furoyl)piperazine

yield: 41 mg (yield: 89%)

HPLC analysis: purity 96.1% (retention time: 3.637 min)

MS (ESI+): 458 (M+H), 460

Example 1781-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-furoyl)piperazine

yield: 20 mg (yield: 50%)

HPLC analysis: purity 98.9% (retention time: 3.352 min)

MS (ESI+): 398 (M+H)

Example 1791-{3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-methylpiperazinetrifluoroacetate

yield: 40 mg (yield: 85%)

HPLC analysis: purity 96.6% (retention time: 2.857 min)

MS (ESI+): 352 (M+H)

Example 1801-{3-[5-(4-bromophenyl)-4-isoxazolyl]propanoyl}-4-methylpiperazinetrifluoroacetate

yield: 43 mg (yield: 87%)

HPLC analysis: purity 95.7% (retention time: 2.852 min)

MS (ESI+): 378 (M+H), 380

Example 1811-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-methylpiperazinetrifluoroacetate

yield: 32 mg (yield: 74%)

HPLC analysis: purity 93.4% (retention time: 2.574 min)

MS (ESI+): 318 (M+H)

Example 182

A mixture of N′-benzyl-N,N-dimethylethylenediamine (27 mg),3-[5-(4-fluorophenyl)-4-isoxazolyl]propionic acid (24 mg),1-hydroxy-7-aza-1H-1,2,3-benzotriazole (20 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (23 mg) andN,N-dimethylformamide (0.3 ml) was stirred at room temperatureovernight. The reaction mixture was directly introduced into preparativeHPLC and purified to giveN-benzyl-N-[2-(dimethylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate.

yield: 47 mg (yield 92%)

HPLC analysis: purity 93.8% (retention time: 2.481 min)

MS (APCI+): 396 (M+H)

In the same manner as in Example 182, the following compounds weresynthesized.

Example 183 N-butyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 21 mg (yield 71%)

HPLC analysis: purity 97.9% (retention time: 3.463 min)

MS (APCI+): 291 (M+H)

Example 184N-(cyclohexylmethyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 23 mg (yield 71%)

HPLC analysis: purity 95.2% (retention time: 3.870 min)

MS (APCI+): 331 (M+H)

NMR (CDCl₃) δ: 0.8-1.8 (11H, m), 2.46 (2H, t, J=7 Hz), 2.95-3.1 (4H, m),5.40 (1H, br s), 7.15-7.25 (2H, m), 7.7-7.8 (2H, m), 8.21 (1H, s).

Example 185N-cyclopropyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 20 mg (yield 73%)

HPLC analysis: purity 97.0% (retention time: 3.031 min)

MS (APCI+): 275 (M+H)

Example 186 N-benzyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 23 mg (yield 71%)

HPLC analysis: purity 95.4% (retention time: 3.566 min)

MS (APCI+): 325 (M+H)

Example 187N-(1,3-benzodioxol-5-ylmethyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 27 mg (yield 73%)

HPLC analysis: purity 97.2% (retention time: 3.507 min)

MS (APCI+): 369 (M+H)

Example 1883-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-phenylethyl)propionamide

yield: 25 mg (yield 74%)

HPLC analysis: purity 98.4% (retention time: 3.680 min)

MS (APCI+): 339 (M+H)

Example 189 3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(3-phenylpropyl)propionamide

yield: 25 mg (yield 71%)

HPLC analysis: purity 98.9% (retention time: 3.822 min)

MS (APCI+): 353 (M+H)

Example 190 N-benzhydryl-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 23 mg (yield 57%)

HPLC analysis: purity 98.4% (retention time: 4.051 min)

MS (APCI+): 401 (M+H)

Example 1913-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-methoxyethyl)propionamide

yield: 21 mg (yield 72%)

HPLC analysis: purity 99.4% (retention time: 2.904 min)

MS (APCI+): 293 (M+H)

Example 1923-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(methylsulfanyl)propyl]propionamide

yield: 23 mg (yield 70%)

HPLC analysis: purity 97.9% (retention time: 3.345 min)

MS (APCI+): 323 (M+H)

Example 1933-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(tetrahydro-2-furanylmethyl)propionamide

yield: 21 mg (yield 65%)

HPLC analysis: purity 98.1% (retention time: 3.057 min)

MS (APCI+): 319 (M+H)

Example 1943-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[2-(1H-indol-3-yl)ethyl]propionamide

yield: 34 mg (yield 89%)

HPLC analysis: purity 99.7% (retention time: 3.657 min)

MS (APCI+): 378 (M+H)

Example 195N-(2-ethylpropyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 22 mg (yield 71%)

HPLC analysis: purity 98.8% (retention time: 3.566 min)

MS (APCI+): 305 (M+H)

Example 196N-(tert-butyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 23 mg (yield 80%)

HPLC analysis: purity 98.7% (retention time: 3.548 min)

MS (APCI+): 291 (M+H)

Example 197 N-cyclohexyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 24 mg (yield 76%)

HPLC analysis: purity 96.8% (retention time: 3.672 min)

MS (APCI+): 317 (M+H)

Example 1983-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-propynyl)propionamide

yield: 20 mg (yield 72%)

HPLC analysis: purity 99.2% (retention time: 3.092 min)

MS (APCI+): 273 (M+H)

Example 1993-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[4-(trifluoromethyl)benzyl]propionamide

yield: 28 mg (yield 73%)

HPLC analysis: purity 99.2% (retention time: 3.913 min)

MS (APCI+): 393 (M+H)

NMR (CDCl₃) δ: 2.54 (2H, t, J=7 Hz), 3.04 (2H, t, J=7 Hz), 4.47 (2H, d,J=7 Hz), 5.82 (1H, br s), 7.1-7.4 (4H, m), 7.57 (2H, d, J=8 Hz),7.65-7.8 (2H, m), 8.20 (1H, s).

Example 200N-[2-(3,4-dimethoxyphenyl)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 29 mg (yield 73%)

HPLC analysis: purity 99.1% (retention time: 3.454 min)

MS (APCI+): 399 (M+H)

Example 201N-(3,3-diphenylpropyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 30 mg (yield 70%)

HPLC analysis: purity 99.4% (retention time: 4.173 min)

MS (APCI+): 429 (M+H)

Example 202N-(2,3-dihydro-1H-inden-2-yl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 26 mg (yield 75%)

HPLC analysis: purity 98.9% (retention time: 3.763 min)

MS (APCI+): 351 (M+H)

Example 2033-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(3-isopropoxypropyl)propionamide

yield: 24 mg (yield 71%)

HPLC analysis: purity 99.4% (retention time: 3.375 min)

MS (APCI−): 333 (M−H)

Example 2043-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-oxo-3-azepanyl)propionamide

yield: 25 mg (yield 72%)

HPLC analysis: purity 97.5% (retention time: 2.953 min)

MS (APCI+): 346 (M+H)

Example 2053-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-furylmethyl)propionamide

yield: 23 mg (yield 73%)

HPLC analysis: purity 99.4% (retention time: 3.364 min)

MS (APCI−): 313 (M−H)

Example 2063-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]propionamide

yield: 29 mg (yield 80%)

HPLC analysis: purity 99.5% (retention time: 2.847 min)

MS (APCI+): 360 (M+H)

Example 2073-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methyl-N-(1-naphthylmethyl)propionamide

yield: 24 mg (yield 62%)

HPLC analysis: purity 99.8% (retention time: 4.165 min)

MS (APCI+): 389 (M+H)

Example 208N-[2-(3,4-dimethoxyphenyl)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methylpropionamide

yield: 25 mg (yield 61%)

HPLC analysis: purity 98.1% (retention time: 3.626 min)

MS (ESI+): 413 (M+H)

Example 2093-[5-(4-fluorophenyl)-4-isoxazolyl]-N,N-bis(2-methoxyethyl)propionamide

yield: 23 mg (yield 66%)

HPLC analysis: purity 99.6% (retention time: 3.353 min)

MS (ESI+): 351 (M+H)

Example 210 1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperidine

yield: 29 mg (yield 96%)

HPLC analysis: purity 99.6% (retention time: 3.566 min)

MS (APCI+): 303 (M+H)

Example 2114-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-2,6-dimethylmorpholine

yield: 31 mg (yield 93%)

HPLC analysis: purity 99.7% (retention time: 3.423 min)

MS (APCI+): 333 (M+H)

NMR (CDCl₃) δ: 1.18 (6H, t, J=7 Hz), 2.25-2.4 (1H, m), 2.5-2.8 (3H, m),3.02 (2H, t, J=7 Hz), 3.4-3.6 (3H, m), 4.4-4.5 (1H, m), 7.15-7.25 (2H,m), 7.7-7.8 (2H, m), 8.24 (1H, s).

Example 2122-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-1,2,3,4-tetrahydroisoquinoline

yield: 26 mg (yield 75%)

HPLC analysis: purity 99.0% (retention time: 3.902 min)

MS (APCI+): 351 (M+H)

Example 2131-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinecarboxyamide

yield: 39 mg (yield 90%)

HPLC analysis: purity 99.5% (retention time: 2.792 min)

MS (APCI+): 346 (M+H)

Example 2142-(1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinyl)ethanol

yield: 27 mg (yield 77%)

HPLC analysis: purity 96.2% (retention time: 3.086 min)

MS (APCI+): 347 (M+H)

Example 2154-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}thiomorpholine

yield: 23 mg (yield 72%)

HPLC analysis: purity 99.4% (retention time: 3.496 min)

MS (APCI+): 321 (M+H)

Example 2164-benzyl-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperidine

yield: 8 mg (yield 21%)

HPLC analysis: purity 99.8% (retention time: 4.273 min)

MS (APCI+): 393 (M+H)

Example 2173-acetamide-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}pyrrolidine

yield: 28 mg (yield 80%)

HPLC analysis: purity 99.7% (retention time: 2.779 min)

MS (APCI+): 346 (M+H)

Example 218N-cyclohexyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methylpropionamide

yield: 19 mg (yield 58%)

HPLC analysis: purity 99.5% (retention time: 3.966 min)

MS (APCI+): 331 (M+H)

Example 219N-benzyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methylpropionamide

yield: 28 mg (yield 83%)

HPLC analysis: purity 99.5% (retention time: 3.837 min)

MS (APCI+): 339 (M+H)

Example 220N-benzyl-N-[2-(ethoxycarbonyl)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 25 mg (yield 60%)

HPLC analysis: purity 98.8% (retention time: 4.068 min)

MS (APCI+): 425 (M+H)

Example 221N-ethyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-methoxyethyl)propionamide

yield: 34 mg (yield 90%)

HPLC analysis: purity 99.5% (retention time: 3.410 min)

MS (APCI−): 319 (M−H)

Example 222 1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}morpholine

yield: 47 mg (yield 90%)

HPLC analysis: purity 97.0% (retention time: 3.070 min)

MS (APCI+): 305 (M+H)

NMR (CDCl₃) δ: 2.60 (2H, t, J=7 Hz), 3.03 (2H, t, J=7 Hz), 3.35-3.45(2H, m), 3.55-3.7 (6H, m), 7.15-7.25 (2H, m), 7.7-7.8 (2H, m), 8.23 (1H,s).

Example 2231-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-3,5-dimethylpiperidine

yield: 44 mg (yield 90%)

HPLC analysis: purity 99.5% (retention time: 4.029 min)

MS (APCI+): 331 (M+H)

NMR (CDCl₃) δ: 0.7-0.9 (6H, m), 1.3-1.5 (1H, m), 1.7-2.0 (2H, m),2.35-2.65 (3H, m), 2.9-3.1 (3H, m), 3.3-3.8 (2H, m), 4.5-4.7 (1H, m),7.1-7.25 (2H, m), 7.65-7.8 (2H, m), 8.23 (1H, s).

Example 2242-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}decahydroisoquinoline

yield: 28 mg (yield 78%)

HPLC analysis: purity 90.1% (retention time: 2.861 min)

MS (APCI+): 357 (M+H)

Example 2254-(ethoxycarbonyl)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperidine

yield: 33 mg (yield 88%)

HPLC analysis: purity 99.1% (retention time: 3.614 min)

MS (APCI+): 375 (M+H)

Example 226N-(2,6-dimethylphenyl)-N-[((2S)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}pyrrolidinyl)methyl]amine

yield: 7 mg (yield 18%)

HPLC analysis: purity 97.8% (retention time: 3.186 min)

MS (APCI+): 422 (M+H)

Example 2274-(4-chlorophenyl)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol

yield: 9 mg (yield 21%)

HPLC analysis: purity 99.7% (retention time: 3.817 min)

MS (APCI−): 427 (M−H)

Example 2283-(N-acetyl-N-ethylamino)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}pyrrolidine

yield: 14 mg (yield 36%)

HPLC analysis: purity 97.0% (retention time: 3.055 min)

MS (APCI+): 374 (M+H)

Example 229N-[2-(dimethylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methylpropionamidetrifluoroacetate

yield: 39 mg (yield 89%)

HPLC analysis: purity 99.8% (retention time: 2.481 min)

MS (APCI−): 318 (M−H)

Example 230N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methylpropionamidetrifluoroacetate

yield: 49 mg (yield 93%)

HPLC analysis: purity 94.5% (retention time: 2.980 min)

MS (APCI+): 408 (M+H)

Example 231N-ethyl-3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(4-pyridinylmethyl)propionamidetrifluoroacetate

yield: 43 mg (yield 91%)

HPLC analysis: purity 99.5% (retention time: 2.637 min)

MS (APCI+): 354 (M+H)

Example 2323-[5-(4-fluorophenyl)-4-isoxazolyl]-N,N-bis(3-pyridinylmethyl)propionamide2-trifluoroacetate

yield: 57 mg (yield 90%)

HPLC analysis: purity 99.7% (retention time: 2.193 min)

MS (APCI+): 417 (M+H)

Example 2331-ethyl-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 42 mg (yield 93%)

HPLC analysis: purity 99.6% (retention time: 2.473 min)

MS (APCI+): 332 (M+H)

Example 2341-(ethoxycarbonylmethyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 43 mg (yield 86%)

HPLC analysis: purity 99.7% (retention time: 2.627 min)

MS (APCI+): 390 (M+H)

Example 2351-benzyl-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 41 mg (yield 80%)

HPLC analysis: purity 98.6% (retention time: 2.834 min)

MS (APCI+): 394 (M+H)

Example 2361-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-pyridinyl)piperazinetrifluoroacetate

yield: 47 mg (yield 96%)

HPLC analysis: purity 99.6% (retention time: 2.598 min)

MS (APCI+): 381 (M+H)

Example 2371-benzhydryl-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 59 mg (yield 96%)

HPLC analysis: purity 99.2% (retention time: 3.202 min)

MS (APCI−): 468 (M−H)

Example 2381-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-phenylpiperazinetrifluoroacetate

yield: 40 mg (yield 81%)

HPLC analysis: purity 98.5% (retention time: 3.456 min)

MS (APCI+): 380 (M+H)

Example 2391-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-methoxyphenyl)piperazinetrifluoroacetate

yield: 47 mg (yield 89%)

HPLC analysis: purity 99.5% (retention time: 3.140 min)

MS (APCI+): 410 (M+H)

Example 2401-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(1-piperidinyl)piperidinetrifluoroacetate

yield: 48 mg (yield 96%)

HPLC analysis: purity 99.2% (retention time: 2.578 min)

MS (APCI+): 386 (M+H)

Example 2413-[5-(4-fluorophenyl)-4-isoxazolyl]-N-methyl-N-(1-methyl-3-pyrrolidinyl)propionamidetrifluoroacetate

yield: 40 mg (yield 90%)

HPLC analysis: purity 99.4% (retention time: 2.494 min)

MS (APCI+): 332 (M+H)

Example 242N-benzyl-N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 54 mg (yield 90%)

HPLC analysis: purity 97.0% (retention time: 3.378 min)

MS (APCI+): 484 (M+H)

Example 2433-[5-(4-fluorophenyl)-4-isoxazolyl]-N,N-bis(2-pyridinylmethyl)propionamide2-trifluoroacetate

yield: 48 mg (yield 80%)

HPLC analysis: purity 99.0% (retention time: 2.606 min)

MS (APCI+): 417 (M+H)

Example 2441-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-hydroxyethyl)piperazinetrifluoroacetate

yield: 36 mg (yield 79%)

HPLC analysis: purity 99.6% (retention time: 2.390 min)

MS (APCI+): 348 (M+H)

Example 2451-(1,3-benzodioxol-5-ylmethyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 58 mg (yield 95%)

HPLC analysis: purity 98.4% (retention time: 2.864 min)

MS (APCI+): 438 (M+H)

Example 2461-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-pyrimidinyl)piperazinetrifluoroacetate

yield: 43 mg (yield 86%)

HPLC analysis: purity 99.1% (retention time: 3.054 min)

MS (APCI+): 382 (M+H)

Example 2471-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-[(E)-3-phenyl-2-propenyl]piperazinetrifluoroacetate

yield: 48 mg (yield 91%)

HPLC analysis: purity 96.9% (retention time: 3.064 min)

MS (APCI+): 420 (M+H)

Example 248(2S)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-2-(1-pyrrolidinylmethyl)pyrrolidinetrifluoroacetate

yield: 44 mg (yield 91%)

HPLC analysis: purity 99.5% (retention time: 2.701 min)

MS (APCI+): 372 (M+H)

Example 2491-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(1-pyrrolidinyl)piperidinetrifluoroacetate

yield: 44 mg (yield 91%)

HPLC analysis: purity 99.4% (retention time: 2.530 min)

MS (APCI+): 372 (M+H)

Example 2501-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-[3-(trifluoromethyl)phenyl]piperazinetrifluoroacetate

yield: 34 mg (yield 61%)

HPLC analysis: purity 99.6% (retention time: 4.229 min)

MS (APCI+): 448 (M+H)

Example 2511-(4-acetylphenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 35 mg (yield 65%)

HPLC analysis: purity 100% (retention time: 3.619 min)

MS (APCI+): 422. (M+H)

Example 2521-(2-chlorophenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 37 mg (yield 71%)

HPLC analysis: purity 99.1% (retention time: 4.176 min)

MS (APCI+): 414 (M+H)

Example 2531-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(3-methoxyphenyl)piperazinetrifluoroacetate

yield: 52 mg (yield 98%)

HPLC analysis: purity 99.6% (retention time: 3.625 min)

MS (APCI+): 410 (M+H)

Example 2541-(3-chlorophenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 27 mg (yield 51%)

HPLC analysis: purity 98.8% (retention time: 4.149 min)

MS (APCI+): 414 (M+H)

Example 2551-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(2-methylphenyl)piperazinetrifluoroacetate

yield: 11 mg (yield 22%)

HPLC analysis: purity 97.7% (retention time: 4.004 min)

MS (APCI+): 394 (M+H)

Example 2561-(2-ethoxyphenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 40 mg (yield 75%)

HPLC analysis: purity 99.2% (retention time: 3.336 min)

MS (APCI+): 424 (M+H)

Example 2571-(2-fluorophenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 34 mg (yield 67%)

HPLC analysis: purity 99.4% (retention time: 3.956 min)

MS (APCI+): 398 (M+H)

Example 2581-(4-chlorophenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 28 mg (yield 53%)

HPLC analysis: purity 99.5% (retention time: 4.084 min)

MS (APCI+): 414 (M+H)

Example 2591-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(4-methoxyphenyl)piperazinetrifluoroacetate

yield: 24 mg (yield 45%)

HPLC analysis: purity 99.2% (retention time: 3.085 min)

MS (APCI+): 410 (M+H)

Example 2601-(4-fluorophenyl)-4-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperazinetrifluoroacetate

yield: 30 mg (yield 58%)

HPLC analysis: purity 99.0% (retention time: 3.643 min)

MS (APCI+): 398 (M+H)

NMR (CDCl₃) δ: 2.66 (2H, t, J=7 Hz), 3.0-3.1 (6H, m), 3.57 (2H, m, J=5Hz), 3.79 (2H, m, J=5 Hz), 6.85-7.0 (4H, m), 7.15-7.25 (2H, m), 7.7-7.8(2H, m), 8.25 (1H, s).

Example 2611-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-(3-methylphenyl)piperazinetrifluoroacetate

yield: 32 mg (yield 63%)

HPLC analysis: purity 89.6% (retention time: 3.545 min)

MS (APCI+): 394 (M+H)

Example 2622-ethyl-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperidine

yield: 27 mg (yield 80%)

HPLC analysis: purity 98.9% (retention time: 3.916 min)

MS (APCI+): 331 (M+H)

Example 2631-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-3-piperidinecarboxyamide

yield: 30 mg (yield 86%)

HPLC analysis: purity 99.1% (retention time: 2.860 min)

MS (APCI+): 346 (M+H)

Example 2641-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-phenyl-4-piperidinol

yield: 32 mg (yield 82%)

HPLC analysis: purity 99.3% (retention time: 3.541 min)

MS (APCI−): 393 (M−H)

Example 2654-(4-bromophenyl)-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-piperidinol

yield: 37 mg (yield 79%)

HPLC analysis: purity 99.2% (retention time: 3.867 min)

MS (APCI−): 471 (M−H), 473

Example 266 1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}azepane

yield: 25 mg (yield 79%)

HPLC analysis: purity 99.0% (retention time: 3.709 min)

MS (APCI+): 317 (M+H)

Example 267 1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}azocane

yield: 27 mg (yield 81%)

HPLC analysis: purity 99.2% (retention time: 3.881 min)

MS (APCI+): 331 (M+H)

Example 2681-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}decahydroquinoline

yield: 30 mg (yield 84%)

HPLC analysis: purity 98.9% (retention time: 4.166 min)

MS (APCI+): 357 (M+H)

Example 2691-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-phenyl-4-piperidinecarbonitrile

yield: 35 mg (yield 86%)

HPLC analysis: purity 98.9% (retention time: 3.929 min)

MS (APCI+): 404 (M+H)

Example 2704-acetyl-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}-4-phenylpiperidine

yield: 17 mg (yield 41%)

HPLC analysis: purity 99.0% (retention time: 3.898 min)

MS (APCI+): 421 (M+H)

Example 2712-ethoxycarbonyl-1-{3-[5-(4-fluorophenyl)-4-isoxazolyl]propanoyl}piperidine

yield: 23 mg (yield 64%)

HPLC analysis: purity 98.3% (retention time: 3.693 min)

MS (APCI+): 361 (M+H)

Example 272N-[2-(dimethylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 20 mg (yield 47%)

HPLC analysis: purity 99.9% (retention time: 2.516 min)

MS (ESI+): 306 (M+H)

Example 273N-[3-(diethylamino)propyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 34 mg (yield 75%)

HPLC analysis: purity 99.8% (retention time: 2.567 min)

MS (ESI+): 348 (M+H)

Example 2743-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[2-(1-piperidinyl)ethyl]propionamidetrifluoroacetate

yield: 34 mg (yield 73%)

HPLC analysis: purity 99.8% (retention time: 2.621 min)

MS (ESI+): 346 (M+H)

Example 2753-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[2-(4-morpholinyl)ethyl]propionamidetrifluoroacetate

yield: 33 mg (yield 71%)

HPLC analysis: purity 99.7% (retention time: 2.499 min)

MS (ESI+): 348 (M+H)

Example 2763-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(4-methyl-1-piperazinyl)propyl]propionamide2-trifluoroacetate

yield: 27 mg (yield 45%)

HPLC analysis: purity 99.7% (retention time: 2.282 min)

MS (ESI+): 375 (M+H)

NMR (CDCl₃) δ: 1.6-1.75 (2H, m), 2.45 (2H, t, J=7 Hz), 2.79 (3H, s),2.8-2.9 (4H, m), 3.0-3.1 (4H, m), 7.35-7.45 (2H, m), 7.75-7.85 (2H, m),8.02 (1H, br s), 8.52 (1H, s).

Example 2773-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(methylanilino)propyl]propionamidetrifluoroacetate

yield: 39 mg (yield 78%)

HPLC analysis: purity 99.8% (retention time: 2.842 min)

MS (ESI+): 382 (M+H)

Example 278N-(1-benzyl-4-piperazinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 39 mg (yield 74%)

HPLC analysis: purity 99.9% (retention time: 2.863 min)

MS (ESI+): 408 (M+H)

Example 2793-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)propionamidetrifluoroacetate

yield: 23 mg (yield 48%)

HPLC analysis: purity 100% (retention time: 2.661 min)

MS (ESI+): 374 (M+H)

NMR (CDCl₃) δ: 1.25-1.4 (12H, m), 1.7-1.9 (2H, m), 2.43 (2H, t, J=7 Hz),2.86 (2H, t, J=7 Hz), 3.55-3.65 (2H, m), 4.0-4.1 (1H, m), 7.35-7.45 (2H,m), 7.7-7.8 (1H, m), 7.75-7.85 (2H, m), 7.95-8.05 (1H, m), 8.51 (1H, s),8.5-8.6 (1H, m).

Example 280N-(2-anilinoethyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 35 mg (yield 76%)

HPLC analysis: purity 99.7% (retention time: 3.002 min)

MS (ESI+): 354 (M+H)

Example 2813-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-pyridinylmethyl)propionamidetrifluoroacetate

yield: 27 mg (yield 62%)

HPLC analysis: purity 99.9% (retention time: 2.497 min)

MS (ESI+): 326 (M+H)

Example 2823-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[2-(4-pyridinyl)ethyl]propionamidetrifluoroacetate

yield: 32 mg (yield 72%)

HPLC analysis: purity 99.9% (retention time: 2.454 min)

MS (ESI+): 340 (M+H)

Example 2833-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(1-imidazolyl)propyl]propionamidetrifluoroacetate

yield: 31 mg (yield 68%)

HPLC analysis: purity 99.9% (retention time: 2.496 min)

MS (ESI+): 343 (M+H)

Example 284N-[2-(diisopropylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 33 mg (yield 69%)

HPLC analysis: purity 99.8% (retention time: 2.733 min)

MS (ESI+): 362 (M+H)

Example 285N-[3-(dimethylamino)-2,2-dimethylpropyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 32.1 mg (yield 70%)

HPLC analysis: purity 99.9% (retention time: 2.570 min)

MS (ESI+): 348 (M+H)

Example 2863-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(2-methyl-1-piperidinyl)propyl]propionamidetrifluoroacetate

yield: 35 mg (yield 71%)

HPLC analysis: purity 100% (retention time: 2.696 min)

MS (ESI+): 374 (M+H)

Example 2873-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(4-morpholinyl)propyl]propionamidetrifluoroacetate

yield: 35 mg (yield 74%)

HPLC analysis: purity 100% (retention time: 2.512 min)

MS (ESI+): 362 (M+H)

Example 2883-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[2-(1-pyrrolidinyl)ethyl]propionamidetrifluoroacetate

yield: 31 mg (yield 69%)

HPLC analysis: purity 99.9% (retention time: 2.542 min)

MS (ESI+): 332 (M+H)

Example 289N-[2-(ethyl-3-methylanilino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 39 mg (yield 77%)

HPLC analysis: purity 99.5% (retention time: 3.054 min)

MS (ESI+): 396 (M+H)

Example 290N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 38 mg (yield 74%)

HPLC analysis: purity 99.7% (retention time: 2.922 min)

MS (ESI+): 394 (M+H)

Example 291N-{3-[bis(2-hydroxyethyl)amino]propyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamidetrifluoroacetate

yield: 34 mg (yield 68%)

HPLC analysis: purity 99.9% (retention time: 2.417 min)

MS (ESI+): 380 (M+H)

Example 2923-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(4-pyridinylmethyl)propionamidetrifluoroacetate

yield: 46 mg (yield 95%)

HPLC analysis: purity 100% (retention time: 2.466 min)

MS (ESI+): 326 (M+H)

Example 2933-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(3-pyridinylmethyl)propionamidetrifluoroacetate

yield: 31 mg (yield 71%)

HPLC analysis: purity 99.9% (retention time: 2.456 min)

MS (ESI+): 326 (M+H)

Example 2943-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[2-(3-pyridinyl)ethyl]propionamidetrifluoroacetate

yield: 35 mg (yield 78%)

HPLC analysis: purity 100% (retention time: 2.489 min)

MS (ESI+): 340 (M+H)

Example 295N-[2-(dimethylamino)ethyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 5 mg (yield 20%)

HPLC analysis: purity 100% (retention time: 2.931 min)

MS (ESI+): 356 (M+H)

Example 296N-[3-(methylanilino)propyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 3 mg (yield 10%)

HPLC analysis: purity 92.9% (retention time: 3.212 min)

MS (ESI+): 432 (M+H)

Example 297N-(1-benzyl-4-piperidinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 11 mg (yield 39%)

HPLC analysis: purity 100% (retention time: 3.213 min)

MS (ESI+): 458 (M+H)

Example 298N-(2,2,6,6-tetramethyl-4-piperidinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 8 mg (yield 28%)

HPLC analysis: purity 100% (retention time: 3.069 min)

MS (ESI+): 424 (M+H)

Example 299N-(2-anilinoethyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 7 mg (yield 13%)

HPLC analysis: purity 92.2% (retention time: 3.387 min)

MS (ESI+): 404 (M+H)

Example 300N-(2-pyridinylmethyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 11 mg (yield 48%)

HPLC analysis: purity 99.9% (retention time: 2.949 min)

MS (ESI+): 376 (M+H)

Example 301N-[2-(4-pyridinyl)ethyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 10 mg (yield 41%)

HPLC analysis: purity 100% (retention time: 2.899 min)

MS (ESI+): 390 (M+H)

Example 302N-[3-(1-imidazolyl)propyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 13 mg (yield 50%)

HPLC analysis: purity 100% (retention time: 2.928 min)

MS (ESI+): 393 (M+H)

Example 303N-[3-(dimethylamino)-2.2-dimethylpropyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 12 mg (yield 45%)

HPLC analysis: purity 100% (retention time: 3.020 min)

MS (ESI+): 398 (M+H)

Example 304N-[3-(2-methyl-1-piperidinyl)propyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 5 mg (yield 20%)

HPLC analysis: purity 100% (retention time: 3.088 min)

MS (ESI+): 424 (M+H)

Example 305N-[2-(ethyl-3-methylanilino)ethyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 4 mg (yield 14%)

HPLC analysis: purity 98.9% (retention time: 3.411 min)

MS (ESI+): 446 (M+H)

Example 306N-(1-benzyl-3-pyrrolidinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 10 mg (yield 34%)

HPLC analysis: purity 100% (retention time: 3.275 min)

MS (ESI+): 444 (M+H)

Example 307N-{3-[bis(2-hydroxyethyl)amino]propyl}-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 7 mg (yield 25%)

HPLC analysis: purity 100% (retention time: 2.854 min)

MS (ESI+): 430 (M+H)

Example 308N-{2-[(5-nitro-2-pyridinyl)amino]ethyl}-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 15 mg (yield 52%)

HPLC analysis: purity 98.1% (retention time: 3.732 min)

MS (ESI+): 450 (M+H)

Example 309N-(4-pyridinylmethyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 8 mg (yield 31%)

HPLC analysis: purity 100% (retention time: 2.907 min)

MS (ESI+): 376 (M+H)

Example 310N-(3-pyridinylmethyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 13 mg (yield 51%)

HPLC analysis: purity 100% (retention time: 2.901 min)

MS (ESI+): 376 (M+H)

Example 311N-[2-(3-pyridinyl)ethyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 13 mg (yield 53%)

HPLC analysis: purity 100% (retention time: 2.916 min)

MS (ESI+): 390 (M+H)

Example 312 3-[5-(4-fluorophenyl)-4-isoxazolyl]-N-phenylpropionamide

yield: 25 mg (yield 79%)

HPLC analysis: purity 100% (retention time: 3.728 min)

MS (ESI+): 311 (M+H)

Example 313N-(2,3-dihydro-5-indenyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 27 mg (yield 78%)

HPLC analysis: purity 99.1% (retention time: 4.100 min)

MS (ESI+): 351 (M+H)

Example 314N-(3,5-dimethoxyphenyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 31 mg (yield 84%)

HPLC analysis: purity 99.5% (retention time: 3.784 min)

MS (ESI+): 371 (M+H)

Example 315N-(4-benzylphenyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 17 mg (yield 43%)

HPLC analysis: purity 99.6% (retention time: 4.307 min)

MS (ESI+): 401 (M+H)

Example 316N-(1,1′-biphenyl-3-yl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 34 mg (yield 87%)

HPLC analysis: purity 97.7% (retention time: 4.300 min)

MS (ESI+): 387 (M+H)

Example 3173-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-thiazolyl)propionamide

yield: 34 mg (yield 90%)

HPLC analysis: purity 97.2% (retention time: 3.346 min)

MS (ESI+): 318 (M+H)

Example 3183-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(4-pyridinyl)propionamidetrifluoroacetate

yield: 27 mg (yield 63%)

HPLC analysis: purity 98.8% (retention time: 2.646 min)

MS (ESI+): 312 (M+H)

Example 319N-(5,6-dimethyl-1,2,4-triazine-3-yl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 20 mg (yield 59%)

HPLC analysis: purity 98.4% (retention time: 3.081 min)

MS (ESI+): 342 (M+H)

Example 3203-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(6-quinolinyl)propionamidetrifluoroacetate

yield: 40 mg (yield 80%)

HPLC analysis: purity 99.7% (retention time: 2.756 min)

MS (ESI+): 362 (M+H)

Example 321N-(2-benzothiazolyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 22 mg (yield 61%)

HPLC analysis: purity 98.7% (retention time: 3.908 min)

MS (ESI+): 368 (M+H)

Example 322N-(2-fluorophenyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 26 mg (yield 78%)

HPLC analysis: purity 99.5% (retention time: 3.735 min)

MS (ESI+): 329 (M+H)

Example 323N-(2,3-dihydro-1,4-benzodioxyn-6-yl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 30 mg (yield 80%)

HPLC analysis: purity 100% (retention time: 3.608 min)

MS (ESI+): 369 (M+H)

Example 3243-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[4-(trifluoromethyl)phenyl]propionamide

yield: 33 mg (yield 84%)

HPLC analysis: purity 100% (retention time: 4.170 min)

MS (ESI+): 395 (M+H)

Example 3253-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(2-phenoxyphenyl)propionamide

yield: 38 mg (yield 93%)

HPLC analysis: purity 99.1% (retention time: 4.258 min)

MS (ESI+): 403 (M+H)

Example 3263-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(1-phenyl-5-pyrazolyl)propionamide

yield: 19 mg (yield 51%)

HPLC analysis: purity 99.5% (retention time: 3.490 min)

MS (ESI+): 377 (M+H)

Example 3273-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(5-methyl-3-isoxazolyl)propionamide

yield: 10 mg (yield 33%)

HPLC analysis: purity 99.5% (retention time: 3.427 min)

MS (ESI+): 316 (M+H)

Example 3283-[5-(4-fluorophenyl)-4-isoxazolyl]-N-(3-quinolinyl)propionamidetrifluoroacetate

yield: 44 mg (yield 85%)

HPLC analysis: purity 100% (retention time: 2.959 min)

MS (ESI+): 362 (M+H)

Example 329N-phenyl-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 6 mg (yield 35%)

HPLC analysis: purity 98.5% (retention time: 4.174 min)

MS (ESI+): 361 (M+H)

Example 330N-(2,3-dihydro-5-indenyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 7 mg (yield 34%)

HPLC analysis: purity 98.3% (retention time: 4.511 min)

MS (ESI+): 401 (M+H)

Example 331N-(3,4-dichlorophenyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 12 mg (yield 55%)

HPLC analysis: purity 99.5% (retention time: 4.672 min)

MS (ESI+): 429 (M+H)

Example 332N-(3,5-dimethoxyphenyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 12 mg (yield 55%)

HPLC analysis: purity 99.5% (retention time: 4.195 min)

MS (ESI+): 421 (M+H)

Example 333N-(4-benzylphenyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 12 mg (yield 55%)

HPLC analysis: purity 96.7% (retention time: 4.698 min)

MS (ESI+): 451 (M+H)

Example 334N-(1,1′-biphenyl-3-yl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 10 mg (yield 46%)

HPLC analysis: purity 98.2% (retention time: 4.660 min)

MS (ESI+): 437 (M+H)

Example 335N-(2-thiazolyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 3 mg (yield 14%)

HPLC analysis: purity 97.5% (retention time: 3.816 min)

MS (ESI+): 368 (M+H)

Example 336N-(4-pyridinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 12 mg (yield 52%)

HPLC analysis: purity 80.0% (retention time: 3.114 min)

MS (ESI+): 362 (M+H)

Example 337N-(5,6-dimethyl-1,2,4-triazin-3-yl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 5 mg (yield 24%)

HPLC analysis: purity 97.4% (retention time: 3.634 min)

MS (ESI+): 392 (M+H)

Example 338N-(6-quinolinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 12 mg (yield 60%)

HPLC analysis: purity 98.9% (retention time: 3.189 min)

MS (ESI+): 412 (M+H)

Example 339N-(2-benzothiazolyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 6 mg (yield 28%)

HPLC analysis: purity 99.1% (retention time: 4.316 min)

MS (ESI+): 418 (M+H)

Example 340N-(2-fluorophenyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 8 mg (yield 44%)

HPLC analysis: purity 99.4% (retention time: 4.200 min)

MS (ESI+): 379 (M+H)

Example 341N-(2,3-dihydro-1,4-benzodioxyn-6-yl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 10 mg (yield 47%)

HPLC analysis: purity 100% (retention time: 4.056 min)

MS (ESI+): 419 (M+H)

Example 342N-[3,5-bis(trifluoromethyl)phenyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 13 mg (yield 52%)

HPLC analysis: purity 99.1% (retention time: 4.859 min)

MS (ESI+): 497 (M+H)

Example 343N-[4-(trifluoromethoxy)phenyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 9 mg (yield 41%)

HPLC analysis: purity 99.2% (retention time: 4.566 min)

MS (ESI+): 445 (M+H)

Example 344N-(2-phenoxyphenyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 11 mg (yield 48%)

HPLC analysis: purity 99.3% (retention time: 4.680 min)

MS (ESI+): 453 (M+H)

Example 345N-(1-phenyl-5-pyrazolyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 11 mg (yield 52%)

HPLC analysis: purity 100% (retention time: 3.952 min)

MS (ESI+): 427 (M+H)

Example 346N-(5-methyl-3-isoxazolyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 7 mg (yield 40%)

HPLC analysis: purity 99.5% (retention time: 3.921 min)

MS (ESI+): 366 (M+H)

Example 347N-(3-pyridinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamidetrifluoroacetate

yield: 10 mg (yield 41%)

HPLC analysis: purity 86.0% (retention time: 3.046 min)

MS (ESI+): 362 (M+H)

Example 348N-(2-pyrazinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 7 mg (yield 36%)

HPLC analysis: purity 99.0% (retention time: 3.650 min)

MS (ESI+): 363 (M+H)

Example 349N-(3-quinolinyl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 14 mg (yield 68%)

HPLC analysis: purity 99.2% (retention time: 3.395 min)

MS (ESI+): 412 (M+H)

Example 350N-(2,1,3-benzothiadiazol-4-yl)-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 11 mg (yield 52%)

HPLC analysis: purity 100% (retention time: 4.334 min)

MS (ESI+): 419 (M+H)

Example 351N-[4-(diethylphosphono)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide

yield: 36 mg (yield 84%)

HPLC analysis: purity 99.6% (retention time: 4.208 min)

MS (ESI+): 429 (M+H)

Example 352N-[4-(diethylphosphono)phenyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide

yield: 38 mg (yield 83%)

HPLC analysis: purity 100% (retention time: 4.431 min)

MS (ESI+): 463 (M+H)

Example 353N-[4-(diethylphosphono)phenyl]-2-(5-phenyl-4-isoxazolyl)acetamide

yield: 38 mg (yield 91%)

HPLC analysis: purity 94.1% (retention time: 4.136 min)

MS (ESI+): 415 (M+H)

Example 354N-[4-(diethylphosphono)phenyl]-4-(5-phenyl-4-isoxazolyl)butanamide

yield: 34 mg (yield 77%)

HPLC analysis: purity 100% (retention time: 4.258 min)

MS (ESI+): 443 (M+H)

Example 355N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-(5-phenyl-4-isoxazolyl)propionamide

yield: 35 mg (yield 82%)

HPLC analysis: purity 100% (retention time: 3.796 min)

MS (ESI+): 427 (M+H)

Example 3563-[5-(4-chlorophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 17 mg (yield 36%)

HPLC analysis: purity 100% (retention time: 4.035 min)

MS (ESI+): 461 (M+H)

Example 357N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-2-(5-phenyl-4-isoxazolyl)acetamide

yield: 23 mg (yield 55%)

HPLC analysis: purity 100% (retention time: 3.718 min)

MS (ESI+): 413 (M+H)

Example 358N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-4-(5-phenyl-4-isoxazolyl)butanamide

yield: 40 mg (yield 92%)

HPLC analysis: purity 99.1% (retention time: 3.862 min)

MS (ESI+): 441 (M+H)

Example 359N-[4-(dimethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide

yield: 26 mg (yield 63%)

HPLC analysis: purity 100% (retention time: 3.897 min)

MS (ESI+): 415 (M+H)

Example 360N-[4-(dimethylphosphonomethyl)phenyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide

yield: 27 mg (yield 59%)

HPLC analysis: purity 100% (retention time: 4.135 min)

MS (ESI+): 449 (M+H)

Example 361N-[4-(dimethylphosphonomethyl)phenyl]-2-(5-phenyl-4-isoxazolyl)acetamide

yield: 26 mg (yield 64%)

HPLC analysis: purity 100% (retention time: 3.826 min)

MS (ESI+): 401 (M+H)

Example 362N-[4-(dimethylphosphonomethyl)phenyl]-4-(5-phenyl-4-isoxazolyl)butanamide

yield: 26 mg (yield 61%)

HPLC analysis: purity 100% (retention time: 3.960 min)

MS (ESI+): 429 (M+H)

Example 363N-[4-(dimethylphosphonomethyl)phenyl]-3-(3,5-diphenyl-4-isoxazolyl)propionamide

yield: 31 mg (yield 64%)

HPLC analysis: purity 99.9% (retention time: 4.417 min)

MS (ESI+): 491 (M+H)

Example 364N-[4-(dimethylphosphonomethyl)phenyl]-3-[5-(4-methylphenyl)-4-isoxazolyl]propionamide

yield: 30 mg (yield 70%)

HPLC analysis: purity 100% (retention time: 4.074 min)

MS (ESI+): 429 (M+H)

Example 365N-[4-(dimethylphosphonomethyl)phenyl]—3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide

yield: 35 mg (yield 82%)

HPLC analysis: purity 100% (retention time: 3.934 min)

MS (ESI+): 429 (M+H)

Example 366N-[4-(dimethylphosphonomethyl)phenyl]-3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionamide

yield: 32 mg (yield 73%)

HPLC analysis: purity 100% (retention time: 3.914 min)

MS (ESI+): 445 (M+H)

Example 367N-[4-(dimethylphosphonomethyl)phenyl]-3-{5-[4-(trifluoromethyl)phenyl]-4-isoxazolyl}propionamide

yield: 30 mg (yield 63%)

HPLC analysis: purity 99.9% (retention time: 4.293 min)

MS (ESI+): 483 (M+H)

Example 3683-[5-(4-fluorophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 27 mg (yield 44%)

HPLC analysis: purity 97.0% (retention time: 3.274 min)

MS (ESI+): 445 (M+H)

NMR (CDCl₃) δ: 1.8-2.0 (2H, m), 2.70 (2H, t, J=7 Hz), 3.07 (2H, t, J=7Hz), 3.19 (2H, d, J=21 Hz), 4.1-4.2 (2H, m), 4.3-4.5 (2H, m), 7.1-7.25(4H, m), 7.35-7.45 (2H, m), 7.7-7.8 (2H, m), 8.11 (1H, br s), 8.23 (1H,s).

Example 369N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-nitrophenyl)-4-isoxazolyl]propionamide

yield: 44 mg (yield 71%)

HPLC analysis: purity 99.4% (retention time: 3.730 min)

MS (ESI+): 488 (M+H)

NMR (CDCl₃) δ: 1.24 (6H, t, J=7 Hz), 2.75 (2H, t, J=7 Hz) 3.09 (2H, d,J=22 Hz), 3.15 (2H, d, J=7 Hz), 3.9-4.05 (4H, m), 7.1-7.2 (2H, m), 7.36(2H, d, J=8.5 Hz), 7.97 (2H, d, J=8.5 Hz), 8.22 (1H, br s), 8.35-8.4(3H, m).

Example 370N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionamide

yield: 57 mg (yield 90%)

HPLC analysis: purity 99.9% (retention time: 3.502 min)

MS (ESI+): 503 (M+H)

Example 3713-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide

yield: 51 mg (yield 75%)

HPLC analysis: purity 99.9% (retention time: 3.979 min)

MS (ESI+): 539 (M+H), 541

Example 3723-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide

yield: 48 mg (yield 77%)

HPLC analysis: purity 100% (retention time: 3.990 min)

MS (ESI+): 495 (M+H)

Example 3733-[5-(3,5-dichlorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide

yield: 53 mg (yield 82%)

HPLC analysis: purity 99.6% (retention time: 4.180 min)

MS (ESI+): 511 (M+H)

Example 374N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionamide

yield: 37 mg (yield 63%) 0.264

HPLC analysis: purity 100% (retention time: 3.822 min)

MS (ESI+): 479 (M+H)

Example 375N-[4-(dimethylphosphonomethyl)phenyl]-3-[5-(4-nitrophenyl)-4-isoxazolyl]propionamide

yield: 10 mg (yield 17%)

HPLC analysis: purity 98.7% (retention time: 3.476 min)

MS (ESI+): 460 (M+H)

Example 3763-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]-N-[4-(dimethylphosphonomethyl)phenyl]propionamide

yield: 43 mg (yield 72%)

HPLC analysis: purity 99.8% (retention time: 3.237 min)

MS (ESI+): 475 (M+H)

NMR (CDCl₃) δ: 2.67 (2H, t, J=7 Hz), 3.11 (2H, t, J=7 Hz), 3.14 (2H, d,J=22 Hz), 3.64 (3H, s), 3.69 (3H, s), 3.94 (3H, s), 3.95 (3H, s), 6.97(1H, d, J=9 Hz), 7.35-7.55 (4H, m), 7.42 (2H, d, J=8.5 Hz), 7.56 (1H, brs), 8.24 (1H, s).

Example 3773-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]-N-[4-(dimethylphosphonomethyl)phenyl]propionamide

yield: 34 mg (yield 53%)

HPLC analysis: purity 100% (retention time: 3.732 min)

MS (ESI+): 511 (M+H), 513

Example 3783-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]-N-[4-(dimethylphosphonomethyl)phenyl]propionamide

yield: 37 mg (yield 63%)

HPLC analysis: purity 100% (retention time: 3.739 min)

MS (ESI+): 467 (M+H)

Example 3793-[5-(3,5-dichlorophenyl)-4-isoxazolyl]-N-[4-(dimethylphosphonomethyl)phenyl]propionamide

yield: 38 mg (yield 64%)

HPLC analysis: purity 99.8% (retention time: 3.909 min)

MS (ESI+): 483 (M+H)

Example 380N-[4-(diethylphosphono)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 40 mg (yield 64%)

HPLC analysis: purity 99.6% (retention time: 3.680 min)

MS (ESI+): 447 (M+H)

Example 3813-[5-(3,4-difluorophenyl)-4-isoxazolyl]-N-[4-(dimethylphosphonomethyl)phenyl]propionamide

yield: 31 mg (yield 56%)

HPLC analysis: purity 99.8% (retention time: 3.565 min)

MS (ESI+): 451 (M+H)

Example 382N-[4-(diethylphosphono)phenyl]-3-[5-(4-nitrophenyl)-4-isoxazolyl]propionamide

yield: 49 mg (yield 83%)

HPLC analysis: purity 100% (retention time: 3.746 min)

MS (ESI+): 474 (M+H)

Example 383N-[4-(diethylphosphono)phenyl]-3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionamide

yield: 51 mg (yield 83%)

HPLC analysis: purity 99.8% (retention time: 3.528 min)

MS (ESI+): 489 (M+H)

Example 3843-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphono)phenyl]propionamide

yield: 52 mg (yield 79%)

HPLC analysis: purity 99.7% (retention time: 4.011 min)

MS (ESI+): 525 (M+H), 527

Example 3853-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphono)phenyl]propionamide

yield: 51 mg (yield 84%)

HPLC analysis: purity 99.9% (retention time: 4.019 min)

MS (ESI+): 481 (M+H)

NMR (CDCl₃) δ: 1.32 (6H, t, J=7 Hz), 2.73 (2H, t, J=7 Hz) 3.10 (2H, t,J=7 Hz), 4.0-4.2 (4H, m), 7.5-7.8 (8H, m), 8.27 (1H, s).

Example 3863-[5-(3,5-dichlorophenyl)-4-isoxazolyl]-N-[4-(diethylphosphono)phenyl]propionamide

yield: 53 mg (yield 85%)

HPLC analysis: purity 99.8% (retention time: 4.215 min)

MS (ESI+): 497 (M+H)

Example 387N-[4-(dimethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 25 mg (yield 42%)

HPLC analysis: purity 97.9% (retention time: 3.375 min)

MS (ESI+): 433 (M+H)

NMR (CDCl₃) δ: 2.69 (2H, t, J=7 Hz), 3.08 (2H, t, J=7 Hz) 3.10 (2H, d,J=21 Hz), 3.62 (3H, s), 3.66 (3H, s), 7.1-7.2 (4H, m), 7.38 (2H, d,J=8.5 Hz), 7.7-7.75 (2H, m), 8.01 (1H, br s), 8.26 (1H, s).

Example 388N-[4-(diethylphosphono)phenyl]-3-[5-(3,4-difluorophenyl)-4-isoxazolyl]propionamide

yield: 36 mg (yield 62%)

HPLC analysis: purity 100% (retention time: 3.849 min)

MS (ESI+): 465 (M+H)

Example 3893-[5-(4-nitrophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 19 mg (yield 33%)

HPLC analysis: purity 100% (retention time: 3.375 min)

MS (ESI+): 472 (M+H)

Example 3903-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 24 mg (yield 40%)

HPLC analysis: purity 100% (retention time: 3.136 min)

MS (ESI+): 487 (M+H)

Example 3913-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 24 mg (yield 37%)

HPLC analysis: purity 99.9% (retention time: 3.637 min)

MS (ESI+): 523 (M+H), 525

Example 3923-[5-(4-chloro-3-fluorophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 22 mg (yield 37%)

HPLC analysis: purity 100% (retention time: 3.634 min)

MS (ESI+): 479 (M+H)

Example 3933-[5-(3,5-dichlorophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 28 mg (yield 44%)

HPLC analysis: purity 100% (retention time: 3.809 min)

MS (ESI+): 495 (M+H)

Example 394N-benzyl-N-[2-(diethylamino)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 33 mg (yield 57%)

HPLC analysis: purity 98.3% (retention time: 3.184 min)

MS (ESI+): 424 (M+H)

Example 3953-[5-(3,4-difluorophenyl)-4-isoxazolyl]-N-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 20 mg (yield 35%)

HPLC analysis: purity 100% (retention time: 3.462 min)

MS (ESI+): 463 (M+H)

Example 3963-[5-(4-fluorophenyl)-4-isoxazolyl]-N-{4-[(5-methyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}propionamide

yield: 33 mg (yield 52%)

HPLC analysis: purity 97.6% (retention time: 3.419 min)

MS (ESI+): 459 (M+H)

NMR (CDCl₃) δ: 0.84 (3H, t, J=7 Hz), 2.0-2.4 (1H, m), 2.68 (2H, t, J=7Hz), 3.08 (2H, t, J=7 Hz), 3.1-3.25 (2H, m), 3.75-3.85 (1H, m), 4.0-4.2(2H, m), 4.25-4.4 (1H, m), 7.1-7.2 (4H, m), 7.35-7.45 (2H, m), 7.7-7.8(2H, m), 7.95 (1H, br s), 8.27 (1H, s).

Example 397N-{4-[(5,5-dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 33 mg (yield 50%)

HPLC analysis: purity 95.8% (retention time: 3.546 min)

MS (ESI+): 473 (M+H)

NMR (CDCl₃) δ: 1.23 (6H, t, J=7 Hz), 2.69 (2H, t, J=7 Hz) 3.0-3.2 (4H,m), 4.3-4.8 (4H, m), 7.1-7.25 (4H, m), 7.3-7.4 (2H, m), 7.7-7.8 (2H, m),7.8-7.9 (1H, m), 8.28 (1H, s).

Example 398N-{4-[(5,5-diethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 35 mg (yield 50%)

HPLC analysis: purity 100% (retention time: 3.805 min)

MS (ESI+): 501 (M+H)

Example 399N-{4-[(4,6-dimethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 34 mg (yield 52%)

HPLC analysis: purity 97.6% (retention time: 3.505 min)

MS (ESI+): 473 (M+H)

Example 400N-{4-[(5-butyl-5-ethyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 32 mg (yield 44%)

HPLC analysis: purity 98.9% (retention time: 4.130 min)

MS (ESI+): 529 (M+H)

NMR (CDCl₃) δ: 0.7-0.95 (6H, m), 1.0-1.4 (8H, m), 2.68 (2H, t, J=7 Hz),3.07 (2H, t, J=7 Hz), 3.18 (2H, d, J=21 Hz), 3.75-3.9 (2H, m), 4.05-4.2(2H, m), 7.1-7.25 (4H, m), 7.35-7.45 (2H, m), 7.7-7.8 (2H, m), 7.9-8.0(1H, m), 8.27 (1H, s).

Example 401N-{4-[2,2-bis(diethylphosphono)ethenyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 31 mg (yield 37%)

HPLC analysis: purity 100% (retention time: 3.730 min)

MS (ESI+): 609 (M+H)

Example 402N-(4-{[bis(ethylamino)phosphoryl]methyl}phenyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 13 mg (yield 21%)

HPLC analysis: purity 97.3% (retention time: 3.362 min)

MS (ESI+): 459 (M+H)

Example 403N-[4-(diethylphosphonomethyl)-2-methylphenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 37 mg (yield 56%)

HPLC analysis: purity 98.1% (retention time: 3.615 min)

MS (ESI+): 475 (M+H)

Example 404N-[3-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 34 mg (yield 53%)

HPLC analysis: purity 99.7% (retention time: 3.668 min)

MS (ESI+): 461 (M+H)

Example 405N-[2-(diethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 44 mg (yield 69%)

HPLC analysis: purity 96.4% (retention time: 3.789 min)

MS (ESI+): 461 (M+H)

Example 406N-{4-[(5-ethyl-5-methyl-2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 30 mg (yield 44%)

HPLC analysis: purity 98.4% (retention time: 3.672 min)

MS (ESI+): 487 (M+H)

Example 407N-[4-(dibutylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 44 mg (yield 61%)

HPLC analysis: purity 100% (retention time: 4.299 min)

MS (ESI+): 517 (M+H)

Example 408N-[4-(diisopropylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 48 mg (yield 70%)

HPLC analysis: purity 100% (retention time: 3.906 min)

MS (ESI+): 489 (M+H)

Example 409N-{4-[2-(diethylphosphono)ethyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 37 mg (yield 57%)

HPLC analysis: purity 100% (retention time: 3.725 min)

MS (ESI+): 475 (M+H)

Example 410N-{4-[(E)-2-(diethylphosphono)-2-(ethoxycarbonyl)ethenyl]phenyl}-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 9 mg (yield 12%)

HPLC analysis: purity 80.0% (retention time: 3.972 min)

MS (ESI+): 545 (M+H)

Example 411N-[2-(diethylphosphono)ethyl]-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide

yield: 1.2 mg (yield 10%)

HPLC analysis: purity 91.6% (retention time: 3.211 min)

MS (ESI+): 399 (M+H)

Example 4123-[5-(4-fluorophenyl)-4-isoxazolyl]-N-[3-(diethylphosphono)propyl]propionamide

yield: 10 mg (yield 18%)

HPLC analysis: purity 97.4% (retention time: 3.182 min)

MS (ESI+): 413 (M+H)

Example 413

A mixture ofN-[4-(diethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide(221 mg), trimethylsilyl bromide (0.17 ml) and acetonitrile (10 ml) wasstirred at room temperature for 16 hr. The reaction mixture was purifiedby preparative HPLC to giveN-[4-(ethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide(139 mg, 67%). melting point: 80-82° C.

NMR (CDCl₃) δ: 1.27 (3H, t, J=7 Hz), 2.64 (2H, t, J=7 Hz), 3.0-3.2 (4H,m), 3.9-4.1 (2H, m), 7.1-7.2 (3H, m), 7.3-7.4 (2H, m), 7.4-7.6 (4H, m),7.6-7.7 (2H, m), 8.21 (1H, s).

MS (ESI+): 415 (M+H)3-(5-Phenyl-4-isoxazolyl)-N-[4-(phosphonomethyl)phenyl]propionamide wasobtained as a byproduct of the preparative HPLC.

yield: 39 mg (yield 20%) melting point: 162-164° C.

NMR (DMSO) δ: 2.67 (2H, t, J=7 Hz), 2.88 (2H, t, J=21 Hz), 2.96 (2H, t,J=7 Hz), 7.15 (2H, dd, J=8.5/2 Hz), 7.45 (2H, d, J=8.5 Hz), 7.5-7.65(3H, m), 7.76 (2H, dd, J=8.5/2 Hz), 8.56 (1H, s), 9.90 (1H, s).

MS (ESI+): 387 (M+H) Preparation Example 1 (Production of capsules) 1)Compound of Example 68 30 mg 2) Finely divided cellulose 10 mg 3)Lactose 19 mg 4) Magnesium stearate  1 mg Total 60 mg

1), 2), 3) and 4) are admixed and filled into a gelatin capsule.Preparation Example 2 (Production of tablets) 1) Compound of Example 6830 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulosecalcium 44 g 5) Magnesium stearate  1 g 1000 tablets 140 g 

The whole amounts of 1), 2) and 3) and 30 g of 4) are kneaded togetherwith water and the mixture, after vacuum drying, is granulated. Thegranular mixture is admixed with 14 g of 4) and 1 g of 5) and theresulting mixture is tableted using a tableting machine to give 1000tablets each containing 30 mg of compound of Example 68.

INDUSTRIAL APPLICABILITY

Since compounds (I), (Ia) and (II) of the present invention havesuperior insulin secretion promoting action and hypoglycemic action andshow low toxicity, they can be used as agents for the prophylaxis ortreatment of diabetes and the like.

In addition, the isoxazole derivative of the present invention can beused as a glucose-dependent insulin secretagogue that exhibits selectiveinsulin secretion promoting action only in the presence of highconcentration glucose. Therefore, the isoxazole derivative is useful asa safe agent for the prophylaxis or treatment of diabetes, which isassociated with a low risk of vascular complications, induction ofhypoglycemia and the like, which are the negative effects caused byinsulin.

This application is based on a patent application No. 2000-350869 filedin Japan, the contents of which are hereby incorporated by reference.

1. A pharmaceutical composition for the prophylaxis or treatment ofdiabetes, which comprises a compound represented by the formula (Ia)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, provided that when R¹ or R² is3,5-di-tert-butyl-4-hydroxyphenyl and W is C₁₋₄ alkylene, Y should notbe OH, or a salt thereof or a prodrug thereof.
 2. A pharmaceuticalcomposition for the prophylaxis or treatment of impaired glucosetolerance, which comprises a compound represented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, or a salt thereof or a prodrug thereof.
 3. An insulinsecretagogue comprising a compound represented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, or a salt thereof or a prodrug thereof.
 4. Apharmaceutical composition for the prophylaxis or treatment of diabeticcomplications, which comprises a compound represented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, wherein at least one of R¹, R², R³ or Y comprises aheterocycle or a heteroaryl, or a salt thereof or a prodrug thereof. 5.The composition of claim 4, wherein the diabetic complication isneuropathy.
 6. A compound represented by the formula (II)

wherein one of R^(1a) and R^(2a) is a hydrogen atom and the other is anoptionally substituted cyclic group; Wa is a divalent aliphatichydrocarbon group; Y is a group of the formula: —OR³, wherein R³ is ahydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an optionally substitutedacyl group, or Y is an optionally esterified or amidated carboxyl group,wherein at least one of R^(1a), R², R³ or Y comprises a heterocycle or aheteroaryl, provided that when Wa is C₁₋₃ alkylene and Y is a group ofthe formula: —OR³ (wherein R³ is as defined above) or an optionallymethylesterified carboxyl group, R^(1a) should be a hydrogen atom andR^(2a) should be an optionally substituted cyclic group, or a saltthereof.
 7. The compound of claim 6, wherein the optionally substitutedcyclic group represented by R^(1a) or R^(2a) is an optionallysubstituted aromatic group.
 8. The compound of claim 6, wherein R^(1a)is a hydrogen atom and R^(2a) is an optionally substituted cyclic group.9. The compound of claim 8, wherein R^(2a) is an optionally substitutedaromatic group.
 10. The compound of claim 6, wherein Wa is a divalentaliphatic hydrocarbon group having 1 to 4 carbon atoms.
 11. The compoundof claim 6, wherein Y is an optionally amidated carboxyl group.
 12. Aprodrug of the compound of claim
 6. 13. The compound of claim 6, whichisN-{4-[(2-oxide-1,3,2-dioxaphosphinan-2-yl)methyl]phenyl}-3-(5-phenyl-4-isoxazolyl)propionamide;N-benzyl-N-(1-benzyl-3-pyrrolidinyl)-3-[5-(4-fluorophenyl)-4-isoxazolyl]propionamide.14. A pharmaceutical composition comprising the compound of claim 6 or aprodrug thereof.
 15. A glucose-dependent insulin secretagogue comprisingan isoxazole derivative.
 16. A method for the prophylaxis or treatmentof diabetes in a mammal, which comprises administering to said mammal aneffective amount of a compound represented by the formula (Ia)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, provided that when R¹ or R² is3,5-di-tert-butyl-4-hydroxyphenyl and W is C₁₋₄ alkylene, Y should notbe OH, or a salt thereof or a prodrug thereof.
 17. A method for theprophylaxis or treatment of diabetic complication in a mammal, whichcomprises administering to said mammal an effective amount of a compoundrepresented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, wherein at least one of R¹, R², R³ or Y comprises aheterocycle or a heteroaryl, or a salt thereof or a prodrug thereof. 18.A method for the prophylaxis or treatment of impaired glucose tolerancein a mammal, which comprises administering to said mammal an effectiveamount of a compound represented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, or a salt thereof or a prodrug thereof.
 19. A method forpromoting an insulin secretion in a mammal, which comprisesadministering to said mammal an effective amount of a compoundrepresented by the formula (I)

wherein one of R¹ and R² is a hydrogen atom or a substituent and theother is an optionally substituted cyclic group; W is a bond or adivalent aliphatic hydrocarbon group; Y is a group of the formula: —OR³,wherein R³ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group, or Y is an optionally esterified or amidatedcarboxyl group, or a salt thereof or a prodrug thereof. 20-23.(canceled)
 24. A commercial package comprising the pharmaceuticalcomposition for the prophylaxis or treatment of diabetes according toclaim 1 and written matter associated therewith, the written matterstating that the composition can or should be used for the prophylaxisor treatment of diabetes.
 25. A commercial package comprising thepharmaceutical composition for the prophylaxis or treatment of impairedglucose tolerance according to claim 2 and written matter associatedtherewith, the written matter stating that the composition can or shouldbe used for the prophylaxis or treatment of impaired glucose tolerance.26. A commercial package comprising the insulin secretagogue of claim 3and written matter associated therewith, the written matter stating thatthe insulin secretagogue can or should be used for promoting insulinsecretion.
 27. A commercial package comprising the pharmaceuticalcomposition for the prophylaxis or treatment of diabetic complicationsaccording to claim 4 and written matter associated therewith, thewritten matter stating that the composition can or should be used forthe prophylaxis or treatment of diabetic complications.